6-azaindole compounds

ABSTRACT

Disclosed are compounds of Formula (I)N-oxides, or salts thereof, wherein A, G, R1, R5, and n are defined herein. Also disclosed are methods of using such compounds as inhibitors of signaling through Toll-like receptor 7, or 8, or 9, and pharmaceutical compositions comprising such compounds. These compounds are useful in treating inflammatory and autoimmune diseases.

CROSS REFERENCE

This application claims the benefit of U.S. Provisional Application Ser.No. 62/607,507 filed Dec. 19, 2017 which is incorporated herein in itsentirety.

DESCRIPTION

The present invention generally relates to 6-azaindole compounds usefulas inhibitors of signaling through Toll-like receptor 7, 8, or 9 (TLR7,TLR8, TLR9) or combinations thereof. Provided herein are 6-azaindolecompounds, compositions comprising such compounds, and methods of theiruse. The invention further pertains to pharmaceutical compositionscontaining at least one compound according to the invention that areuseful for the treatment of conditions related to TLR modulation, suchas inflammatory and autoimmune diseases, and methods of inhibiting theactivity of TLRs in a mammal.

Toll/IL-1 receptor family members are important regulators ofinflammation and host resistance. The Toll-like receptor familyrecognizes molecular patterns derived from infectious organismsincluding bacteria, fungi, parasites, and viruses (reviewed in Kawai, T.et al., Nature Immunol., 11:373-384 (2010)). Ligand binding to thereceptor induces dimerization and recruitment of adaptor molecules to aconserved cytoplasmic motif in the receptor termed the Toll/IL-1receptor (TIR) domain with the exception of TLR3, all TLRs recruit theadaptor molecule MyD88. The IL-1 receptor family also contains acytoplasmic TIR motif and recruits MyD88 upon ligand binding (reviewedin Sims, J. E. et al., Nature Rev. Immunol., 10:89-102 (2010)).

Toll-like receptors (TLRs) are a family of evolutionarily conserved,transmembrane innate immune receptors that participate in the first-linedefense. As pattern recognition receptors, the TLRs protect againstforeign molecules, activated by pathogen associated molecular patterns(PAMPs), or from damaged tissue, activated by danger associatedmolecular patterns (DAMPs). A total of 13 TLR family members have beenidentified, 10 in human, that span either the cell surface or theendosomal compartment. TLR7/8/9 are among the set that are endosomallylocated and respond to single-stranded RNA (TLR7 and TLR8) orunmethylated single-stranded DNA containing cytosine-phosphate-guanine(CpG) motifs (TLR9).

Activation of TLR7/8/9 can initiate a variety of inflammatory responses(cytokine production, B cell activation and IgG production, Type Iinterferon response). In the case of autoimmune disorders, the aberrantsustained activation of TLR7/8/9 leads to worsening of disease states.Whereas overexpression of TLR7 in mice has been shown to exacerbateautoimmune disease, knockout of TLR7 in mice was found to be protectiveagainst disease in lupus-prone MRL/lpr mice. Dual knockout of TLR7 and 9showed further enhanced protection.

As numerous conditions may benefit by treatment involving modulation ofcytokines, IFN production and B cell activity, it is immediatelyapparent that new compounds capable of modulating TLR7 and/or TLR8and/or TLR9 and methods of using these compounds could providesubstantial therapeutic benefits to a wide variety of patients.

The present invention relates to a new class of 6-azaindole compoundsfound to be effective inhibitors of signaling through TLR7/8/9. Thesecompounds are provided to be useful as pharmaceuticals with desirablestability, bioavailability, therapeutic index, and toxicity values thatare important to their drugability.

SUMMARY OF THE INVENTION

The present invention provides compounds of Formula (I) that are usefulas inhibitors of signaling through Toll-like receptor 7, 8, or 9 and areuseful for the treatment of proliferative diseases, allergic diseases,autoimmune diseases and inflammatory diseases, or stereoisomers,N-oxides, tautomers, pharmaceutically acceptable salts, solvates orprodrugs thereof.

The present invention also provides pharmaceutical compositionscomprising a pharmaceutically acceptable carrier and at least one of thecompounds of the present invention or stereoisomers, tautomers,pharmaceutically acceptable salts, solvates, or prodrugs thereof.

The present invention also provides a method for inhibition of Toll-likereceptor 7, 8, or 9 comprising administering to a host in need of suchtreatment a therapeutically effective amount of at least one of thecompounds of the present invention or stereoisomers, tautomers,pharmaceutically acceptable salts, solvates, or prodrugs thereof.

The present invention also provides a method for treating proliferative,metabolic, allergic, autoimmune and inflammatory diseases, comprisingadministering to a host in need of such treatment a therapeuticallyeffective amount of at least one of the compounds of the presentinvention or stereoisomers, tautomers, pharmaceutically acceptablesalts, solvates, or prodrugs thereof.

The present invention also provides a method of treating a disease ordisorder associated with Toll-like receptor 7, 8, or 9 activity, themethod comprising administering to a mammal in need thereof, at leastone of the compounds of Formula (I) or salts, solvates, and prodrugsthereof.

The present invention also provides processes and intermediates formaking the compounds of Formula (I) including salts, solvates, andprodrugs thereof.

The present invention also provides at least one of the compounds ofFormula (I) or salts, solvates, and prodrugs thereof, for use intherapy.

The present invention also provides the use of at least one of thecompounds of Formula (I) or salts, solvates, and prodrugs thereof, forthe manufacture of a medicament for the treatment of prophylaxis ofToll-like receptor 7, 8, or 9 related conditions, such as allergicdisease, autoimmune diseases, inflammatory diseases, and proliferativediseases.

The compound of Formula (I) and compositions comprising the compounds ofFormula (I) may be used in treating, preventing, or curing variousToll-like receptor 7, 8, or 9 related conditions. Pharmaceuticalcompositions comprising these compounds are useful for treating,preventing, or slowing the progression of diseases or disorders in avariety of therapeutic areas, such as allergic disease, autoimmunediseases, inflammatory diseases, and proliferative diseases.

These and other features of the invention will be set forth in expandedform as the disclosure continues.

DETAILED DESCRIPTION

The first aspect of the present invention provides at least one compoundof Formula (I):

N-oxide, or a salt thereof, wherein:

-   G is:-   (i)

-   (ii)

-   (iii)

-   (iv) a 9-membered heterocyclic ring selected from:

or

-   (v) 10-membered heterocyclic ring selected from:

-   A is:-   (i) —O-L₁-R₆;-   (ii) —NR₇R₈;-   (iii) -L₂-C(O)NR₉R₁₀;-   (iv) —(CR_(x)R_(x))₁₋₃R₁₁, C₁₋₃ aminoalkyl,    —(CR_(x)R_(x))₁₋₃NR_(x)C(O)R₁₁,    —(CR_(x)R_(x))₁₋₂NR_(x)C(O)(CH₂)₁₋₂(piperidinyl),    —(CR_(x)R_(x))₁₋₂NR_(x)C(O)O(CH₂)₁₋₂(piperidinyl), or    —(CR_(x)R_(x))₁₋₂NR_(x)C(O)(CH₂)₁₋₂NR_(x)R_(x);-   (v) —CR_(x)R₁₂R₁₃, wherein R₁₂ and R₁₃ together with the carbon atom    to which they are attached form a cyclic group selected from    azabicyclo[4.1.1]octanyl, azepanyl, azetidinyl, C₃₋₇ cycloalkyl,    diazepanyl, diazaspiro[4.5]decanonyl, morpholinyl,    octahydrocyclopenta[c]pyrrolyl, piperazinyl, piperidinyl,    pyrrolidinyl, and quinuclidinyl, each substituted with zero to 4    R_(12a);-   (vi) —CR_(x)═CR_(x)(piperidinyl); or-   (vii) an aromatic group selected from    [1,2,4]triazolo[1,5-a]pyridinyl, imidazo[1,2-a]pyridinyl,    imidazolyl, indazolyl, isoquinolinyl, oxadiazolyl, oxazolyl, phenyl,    pyrazinyl, pyrazolo[3,4-b]pyridinyl, pyrazolyl, pyridazinyl,    pyridinyl, pyrimidinyl, pyrrolyl, quinolinonyl, quinolinyl,    quinoxalinyl, tetrahydro-[1,2,4]triazolo[1,5-a]pyrazinyl,    tetrahydroimidazo[1,2-a]pyrazinyl, tetrahydroisoquinolinyl,    tetrahydrothiazolo[5,4-c]pyridinyl,    tetrahydrothieno[2,3-c]pyridinyl, thiadiazolyl, thiazolyl,    thiooxadiazolyl, and triazolyl, each substituted with zero to 2    R_(14a) and zero to 3 R_(14b);-   L₁ is bond, —(CR_(x)R_(x))₁₋₂—, —(CR_(x)R_(x))₁₋₂CR_(x)(OH)—,    —(CR_(x)R_(x))₁₂O—, —CR_(x)R_(x)C(O)—,    —CR_(x)R_(x)C(O)NR_(x)(CR_(x)R_(x))₀₋₄—,    —CR_(x)R_(x)NR_(x)C(O)(CR_(x)R_(x))₀₋₄—, or    —CR_(x)R_(x)NR_(x)C(O)(CR_(x)R_(x))₀₋₄—;-   L₂ is a bond or —(CR_(x)R_(x))₁₋₃—;-   R₁ is H, Cl, —CN, C₁₋₄ alkyl, C₁₋₃ fluoroalkyl, C₁₋₃ hydroxyalkyl,    C₁₋₃ hydroxy-fluoroalkyl, —CR_(v)═CH₂, C₃₋₆ cycloalkyl, —CH₂(C₃₋₆    cycloalkyl), —C(O)O(C₁₋₃ alkyl), or tetrahydropyranyl;-   each R₂ is independently halo, —CN, —OH, —NO₂, C₁₋₄ alkyl, C₁₋₂    fluoroalkyl, C₁₋₂ cyanoalkyl, C₁₋₃ hydroxyalkyl, C₁₋₃ aminoalkyl,    —O(CH₂)₁₋₂OH, —(CH₂)₀₋₄O(C₁₋₄ alkyl), C₁₋₃ fluoroalkoxy,    —(CH₂)₁₋₄O(C₁₋₃ alkyl), —O(CH₂)₁₋₂OC(O)(C₁₋₃ alkyl),    —O(CH₂)₁₋₂NR_(x)R_(x), —C(O)O(C₁₋₃ alkyl), —(CH₂)₀₋₂C(O)NR_(y)R_(y),    —C(O)NR_(x)(C₁₋₅ hydroxyalkyl), —C(O)NR_(x)(C₂₋₆ alkoxyalkyl),    —C(O)NR_(x)(C₃₋₆ cycloalkyl), —NR_(y)R_(y), —NR_(y)(C₁₋₃    fluoroalkyl), —NR_(y)(C₁₋₄ hydroxyalkyl), —NR_(x)CH₂(phenyl),    —NR_(x)S(O)₂(C₃₋₆ cycloalkyl), —NR_(x)C(O)(C₁₋₃ alkyl),    —NR_(x)CH₂(C₃₋₆ cycloalkyl), —(CH₂)₀₋₂S(O)₂(C₁₋₃ alkyl),    —(CH₂)₀₋₂(C₃₋₆ cycloalkyl), —(CH₂)₀₋₂(phenyl), morpholinyl,    dioxothiomorpholinyl, dimethyl pyrazolyl, methylpiperidinyl,    methylpiperazinyl, amino-oxadiazolyl, imidazolyl, triazolyl, or    —C(O)(thiazolyl);-   R_(2a) is C₁₋₆ alkyl, C₁₋₃ fluoroalkyl, C₁₋₆ hydroxyalkyl, C₁₋₃    aminoalkyl, —(CH₂)₀₋₄O(C₁₋₃ alkyl), C₃₋₆ cycloalkyl,    —(CH₂)₁₋₃C(O)NR_(x)R_(x), —CH₂(C₃₋₆ cycloalkyl), —CH₂(phenyl),    tetrahydrofuranyl, tetrahydropyranyl, or phenyl;-   each R_(2b) is independently H, halo, —CN, —NR_(x)R_(x), C₁₋₆ alkyl,    C₁₋₃ fluoroalkyl, C₁₋₃ hydroxyalkyl, C₁₋₃ fluoroalkoxy,    —(CH₂)₀₋₂O(C₁₋₃ alkyl), —(CH₂)₀₋₃C(O)NR_(x)R_(x), —(CH₂)₁₋₃(C₃₋₆    cycloalkyl), —C(O)O(C₁₋₃ alkyl), —C(O)NR_(x)(C₁₋₃ alkyl),    —CR_(x)═CR_(x)R_(x), or —CR_(x)═CH(C₃₋₆ cycloalkyl);-   R_(2c) is R_(2a) or R_(2b);-   R_(2d) is R_(2a) or R_(2b); provided that one of R_(2c) and R_(2d)    is R_(2a), and the other of R_(2c) and R₂ is R_(2b);-   each R₅ is independently F, Cl, —CN, C₁₋₃ alkyl, C₁₋₂ fluoroalkyl,    or —OCH₃;-   R₆ is:    -   (i) —CR_(x)R_(x)C(O)NR_(x)(CR_(x)R_(x))₁₋₃OH,        —CR_(x)R_(x)C(O)NR_(x)(CR_(x)R_(x))₁₋₂NR_(x)R_(x), or        —CR_(x)R_(x)C(O)NR_(x)(CR_(x)R_(x))₁₋₂CHFCR_(x)R_(x)OH; or    -   (ii) azabicyclo[3.2.1]octanyl, azaspiro[5.5]undecanyl,        azetidinyl, C₃₋₆ cycloalkyl, diazabicyclo[2.2.1]heptanyl,        diazaspiro[3.5]nonanyl, morpholinyl, tetrahydrofuranyl,        tetrahydropyranyl, octahydrocyclopenta[c]pyrrolyl, piperazinyl,        piperidinyl, pyrrolidinyl, or quinuclidinyl, each substituted        with zero to 3 R_(6a);-   each R_(6a) is independently F, Cl, —OH, —CN, C₁₋₆ alkyl, C₁₋₄    fluoroalkyl, C₁₋₆ hydroxyalkyl, —(CH₂)₁₋₂O(C₁₋₃ alkyl),    —NR_(x)R_(x), —(CH₂)₁₋₂NR_(x)R_(x), —(CR_(x)R_(x))₁₋₂S(O)₂(C₁₋₃    alkyl), —(CR_(x)R_(x))₁₋₂C(O)NR_(x)R_(x),    —C(O)(CR_(x)R_(x))₁₋₂NR_(x)R_(x), oxetanyl, tetrahydrofuranyl,    tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl,    isobutylpiperidinyl, piperazinyl, or —O(piperidinyl);-   R₇ is:    -   (i) R_(7a), —CH₂R_(7a), —C(O)R_(7a), —C(O)CH(NH₂)R_(7a),        —C(O)(CH₂)₁₋₃NH₂, —C(O)CH(NH₂)(C₁₋₄ alkyl),        —C(O)CH(NH₂)(CH₂)₁₋₂C(O)OH, —C(O)CH(NH₂)(CH₂)₂₋₄NH₂, or        —C(O)CH(NH₂)(CH₂)₁₋₃C(O)NH₂; or    -   (ii) C₃₋₆ cycloalkyl substituted with one substituent selected        from —NR_(x)(CH₂)₂₋₃NR_(y)R_(y), —NR_(x)(methylpiperidinyl),        —NR_(x)(CH₂)₂₋₃(morpholinyl), dimethylamino piperidinyl, and        piperazinyl substituted with a substituent selected from C₁₋₄        alkyl, —C(O)CH₃, —(CH₂)₁₋₂OCH₃, —CH₂(methylphenyl),        —(CH₂)₂₋₃(pyrrolidinyl), C₃₋₆ cycloalkyl, pyridinyl, and        methylpiperidinyl;-   R_(7a) is azaspiro[3.5]nonanyl, C₃₋₆ cycloalkyl,    diazaspiro[3.5]nonanyl, diazaspiro[5.5]undecanyl, diazepanonyl,    diazepanyl, morpholinyl, phenyl, piperazinyl, piperidinyl,    pyrrolidinonyl, pyrrolidinyl, or pyrrolyl, each substituted with    zero to 1 substituent selected from C₁₋₃ alkyl, —NH₂,    methylpiperidinyl, methylpyrrolidinyl, —OCH₂CH₂(pyrrolidinyl), and    —OCH₂CH₂NHCH₂CH₃; and zero to 4 substituents selected from —CH₃;-   R_(7b) is:    -   (i) C₁₋₆ alkyl, C₁₋₃ fluoroalkyl, C₁₋₃ cyanoalkyl, C₁₋₅        hydroxyalkyl, —(CH₂)₂₋₃C≡CH, —(CH₂)₁₋₂O(C₁₋₂ alkyl),        —(CH₂)₁₋₂S(O)₂(C₁₋₂ alkyl), —(CH₂)₀₋₃NR_(x)R_(y),        —CH₂C(O)NR_(x)R_(x), —NR_(y)R_(y), —NR_(x)(C₁₋₄ hydroxyalkyl),        —NR_(x)(CR_(x)R_(x)CR_(x)R_(x)O(C₁₋₂ alkyl)), —NR_(y)(C₁₋₂        cyanoalkyl), —NR_(x)(C₁₋₂ fluoroalkyl), —NR_(x)(C₂₋₆        hydroxyfluoroalkyl), —NR_(x)(CH₂)₁₋₂C(O)NR_(x)R_(x),        —NR_(x)(CH₂)₁₋₃NR_(x)R_(x), —NR_(x)CH₂CH₂NR_(x)R_(x),        —NR_(x)C(O)(CH₂)₁₋₂NR_(x)R_(x), —O(CH₂)₁₋₃NR_(x)R_(x),        —C(O)(C₁₋₄ alkyl, —C(O)CH₂NR_(x)R_(x), —S(O)₂(C₁₋₃ alkyl),        —(CH₂)₁₋₂R_(7d), —CR_(x)R_(x)C(O)R_(7d), —C(O)CR_(x)R_(x)R_(7d),        —NHR_(7d), —NH(CH₂)₁₋₂R_(7d), or —OR_(7d); or    -   (ii) azepanyl, azetidinyl, bicyclo[1.1.1]pentanyl, C₃₋₆        cycloalkyl, diazepanyl, dioxothiomorpholinyl, morpholinyl,        oxaazaspiro[3.3]heptanyl, oxetanyl, piperazinonyl, piperazinyl,        piperidinyl, pyridinyl, pyrrolidinonyl, pyrrolidinyl,        tetrahydrofuranyl, tetrahydroisoquinolinyl, or        tetrahydropyranyl, each substituted with zero to 1 R_(8a) and        zero to 3 R_(8b);-   each R_(7c) is independently F, Cl, —CN, C₁₋₂ alkyl, —CF₃, or    —CH₂CN;-   R_(7d) is azaspiro[3.5]nonanyl, bicyclo[1.1.1]pentanyl, C₃₋₆    cycloalkyl, morpholinyl, oxetanyl, phenyl, piperidinyl, pyrazolyl,    pyrrolidinyl, tetrahydrofuranyl, or tetrahydropyranyl, each    substituted with zero to 1 substituent selected from C₁₋₃ alkyl,    —NR_(x)R_(x), —C(O)CH₃, methylpiperidinyl, methylpyrrolidinyl,    tetramethylpiperidinyl, —OCH₂CH₂(pyrrolidinyl), and    —OCH₂CH₂NHCH₂CH₃; and zero to 4 substituents selected from —CH₃;-   R₈ is H or C₁₋₃ alkyl;-   or R₇ and R₈ together with the nitrogen atom to which they are    attached form a heterocyclic ring selected from azetidinyl,    diazepanonyl, diazepanyl, diazaspiro[3.3]heptanyl,    diazaspiro[3.5]nonanyl, diazaspiro[5.5]undecanyl, imidazolyl,    imidazolidinonyl, octahydro-1H-pyrrolo[3,4-b]pyridinyl, piperazinyl,    piperidinyl, pyrrolidinonyl, pyrrolidinyl, and pyrrolyl, wherein    said heterocyclic ring is substituted with zero to 1 R_(7b) and zero    to 2 R_(7c);-   R_(8a) is —OH, C₁₋₆ alkyl, C₁₋₄ fluoroalkyl, C₁₋₄ hydroxyalkyl,    —(CH₂)₁₋₂O(C₁₋₃ alkyl), —C(O)(C₁₋₃ alkyl), —(CH₂)₁₋₂(C₃₋₆    cycloalkyl), —(CH₂)₁₋₃(methyl phenyl), —(CH₂)₁₋₃(pyrrolidinyl),    —(CH₂)₁₋₃(methylpyrazolyl), —(CH₂)₁₋₃(thiophenyl), —NR_(x)R_(x),    C₃₋₆ cycloalkyl, methylpiperidinyl, pyridinyl, or pyrimidinyl;-   each R_(8a) is independently F, Cl, —CN, C₁₋₃ alkyl, or —CF₃;-   R₉ is C₁₋₆ alkyl, C₁₋₆ hydroxyalkyl, C₁₋₆ hydroxy fluoroalkyl, C₁₋₃    aminoalkyl, —(CH₂)₁₋₂O(C₁₋₃ alkyl), —(CH₂)₁₋₃NR_(x)R_(x),    —(CH₂)₁₋₂C(O)NR_(x)R_(x), —(CH₂)₁₋₃S(O)₂OH,    —(CR_(x)R_(x))₁₋₃NR_(x)S(O)₂(C₁₋₂ alkyl), or —(CH₂)₀₋₃R_(9a);-   R_(9a) is C₃₋₇ cycloalkyl, furanyl, phenyl, piperazinyl,    piperidinyl, pyrazolyl, pyridinyl, pyrrolidinyl, quinuclidinyl,    thiazolyl, or octahydrocyclopenta[c]pyrrolyl, each substituted with    zero to 3 substituents independently selected from F, Cl, —OH, C₁₋₄    alkyl, C₁₋₃ hydroxyalkyl, C₁₋₃ hydroxy fluoroalkyl, C₁₋₃ aminoalkyl,    —NR_(y)R_(y), oxetanyl, phenyl, piperazinyl, piperidinyl, and    pyrrolidinyl;-   R₁₀ is H, C₁₋₄ alkyl, —(CH₂)₁₋₃O(C₁₋₂ alkyl), or C₃₋₆ cycloalkyl;-   or R₉ and R₁₀ together with the nitrogen atom to which they are    attached form a heterocyclic ring selected from    azabicyclo[3.1.1]heptanyl, azaspiro[5.5]undecanyl,    diazabicyclo[2.2.1]heptanyl, diazabicyclo[3.1.1]heptanyl,    diazabicyclo[3.2.0]heptanyl, diazaspiro[3.5]nonanyl,    diazaspiro[4.4]nonanyl, diazaspiro[4.5]decanyl, diazepanyl,    indolinyl, morpholinyl, octahydropyrrolo[3,4-c]pyrrolyl,    piperazinonyl, piperazinyl, piperidinyl, and pyrrolidinyl, each    substituted with zero to 3 R_(10a);    -   each R_(10a) is independently C₁₋₄ alkyl, C₁₋₄ hydroxyalkyl,        —(CH₂)₁₋₃O(C₁₋₃ alkyl), —(CH₂)₁₋₃NR_(x)R_(x),        —(CH₂)₁₋₂C(O)NR_(x)R_(x), —(CH₂)₁₋₂(methyltriazolyl),        —CH₂CH₂(phenyl), —CH₂CH₂(morpholinyl), —C(O)(C₁₋₂ alkyl),        —C(O)NR_(y)R_(y), —C(O)CH₂NR_(y)R_(y), —NR_(y)R_(y),        —NHC(O)(C₁₋₃ alkyl), —C(O)(furanyl), —O(piperidinyl),        —C(O)CH₂(diethylcarbamoylpiperidinyl), methylpiperazinyl,        piperidinyl, methylpiperidinyl, diethylcarbamoylpiperidinyl,        isopropylpiperidinyl, pyridinyl, trifluoromethylpyridinyl,        pyrimidinyl, or dihydrobenzo[d]imidazolonyl; Rn is azetidinyl,        azaspiro[3.5]nonanyl, dioxidothiomorpholinyl,        hexahydropyrrolo[3,4-c]pyrrolyl, morpholinyl, piperazinyl,        piperidinyl, pyridinyl, or pyrrolidinyl, each substituted with        zero to 3 substituents independently selected from halo, —CN,        C₁₋₄ alkyl, C₁₋₃ aminoalkyl, —(CH₂)₁₋₂(phenyl),        —C(O)CH₂NR_(x)R_(x), C₁₋₅ hydroxyalkyl,        —(CH₂)₁₋₂C(O)NR_(x)R_(x), —(CH₂)₁₋₂S(O)₂(C₁₋₃ alkyl),        —(CH₂)₁₋₂S(O)(C₁₋₃ alkyl), oxetanyl, tetrahydrofuranyl, and        tetrahydropyranyl;-   each R_(12a) is independently F, Cl, —OH, C₁₋₆ alkyl, C₁₋₄    fluoroalkyl, C₁₋₄ cyanoalkyl, C₁₋₆ hydroxyalkyl, —(CH₂)₁₋₂O(C₁₋₃    alkyl), —(CH₂)₁₋₂C(O)NR_(x)R_(x), —(CH₂)₁₋₂S(O)₂(C₁₋₂ alkyl),    —(CH₂)₁₋₂NR_(x)HS(O)₂(C₁₋₂ alkyl), —(CH₂)₁₋₂NR_(x)R_(x), C₁₋₃    alkoxy, —NR_(y)R_(y), —NR_(x)(C₁₋₄ fluoroalkyl), —NR_(x)(C₁₋₂    cyanoalkyl), —NR_(x)CH₂NR_(x)R_(x), —NR_(x)(C₁₋₄ hydroxyalkyl),    —NR_(x)(C₂₋₆ hydroxyfluoroalkyl),    —NR_(x)(CR_(x)R_(x)CR_(x)R_(x))O(C₁₋₃ alkyl),    —NR_(x)(CH₂C(O)NR_(x)R_(x)), —NR_(x)(C₁₋₃ alkoxy),    —NR_(x)CH₂CH₂S(O)₂(C₁₋₂ alkyl), —NR_(x)C(O)CH₃, —NR_(x)C(O)(C₁₋₂    fluoroalkyl), —NR_(x)C(O)CR_(x)R_(x)NR_(x)R_(x),    —NR_(x)C(O)CH₂NR_(y)R_(y), —NR_(x)C(O)CH₂NR_(x)(C₁₋₄ hydroxyalkyl),    —NR_(x)(CH₂)₁₋₂C(O)NR_(x)R_(x), —NR_(x)S(O)₂(C₁₋₂ alkyl), —C(O)(C₁₋₅    alkyl), —C(O)(CH₂)₁₋₃O(C₁₋₂ alkyl), —C(O)CR_(x)R_(x)NR_(y)R_(y),    R_(12b), —CR_(x)R_(x)R_(12b), —C(O)R_(12b),    —C(O)CR_(x)R_(x)NR_(x)R_(12b), —C(O)NR_(x)R_(12b),    —NR_(x)C(O)CR_(x)R_(x)R_(12b), —NR_(x)R_(12b),    —NR_(x)CR_(x)R_(x)R_(12b), —N(CH₂CN)R_(12b),    —NR_(x)C(O)CR_(x)R_(x)NR_(x)R_(12b),    —NR_(x)C(O)CR_(x)R_(x)NR_(x)CH₂R_(12b),    —NR_(x)CR_(x)R_(x)C(O)NR_(x)R_(12b), or —OR_(12b); or two R_(12a)    and the carbon atom to which they are attached form C═O;-   R_(12b) is azetidinyl, bicyclo[1.1.1]pentanyl, C₃₋₆ cycloalkyl,    diazabicyclo[2.2.1]heptanyl, dioxolanyl,    dioxidotetrahydrothiopyranyl, dioxidothiomorpholinyl, imidazolyl,    morpholinyl, octahydrocyclopenta[c]pyrrolyl,    octahydropyrrolo[3,4-c]pyrrolyl, oxaazaspiro[3.3]heptanyl, oxetanyl,    phenyl, piperazinyl, piperazinonyl, piperidinyl, pyridinyl,    pyrrolidinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydropyranyl,    or triazolyl, each substituted with zero to 4 substituents    independently selected from F, Cl, —OH, C₁₋₄ alkyl, C₁₋₃    fluoroalkyl, C₁₋₃ hydroxyalkyl, C₁₋₃ aminoalkyl, C₁₋₄ alkoxy,    —(CH₂)₁₋₂O(C₁₋₃ alkyl), —NR_(x)R_(x), —C(O)NR_(x)R_(x), and    —CR_(x)R_(x)S(O)₂(C₁₋₃ alkyl);    each R_(14a) is independently is:    -   (i) H, halo, —OH, C₁₋₆ alkyl, C₁₋₂₃ fluoroalkyl, C₁₋₄        hydroxyalkyl, —(CH₂)₀₋₂O(C₁₋₃ alkyl), —CR_(x)R_(x)NR_(y)R_(y),        —CR_(x)R_(x)NR_(x)(C₁₋₃ cyanoalkyl),        —CR_(x)R_(x)NR_(x)((CH₂)₁₋₂O(C₁₋₂ alkyl)),        —CR_(x)R_(x)N((CH₂)₁₋₂OCH₃)₂, —CR_(x)R_(x)NR_(x)(CH₂C≡CR_(x)),        —CR_(x)R_(x)NR_(x)(CH₂)₁₋₃NR_(x)R_(x),        —(CR_(x)R_(x))₁₋₃CR_(x)R_(x)NR_(x)R_(x),        —CR_(x)(NH₂)(CH₂)₁₋₄NR_(x)R_(x),        —CR_(x)R_(x)NR_(x)(CH₂)₁₋₂O(C₁₋₃ alkyl),        —CR_(x)R_(x)NR_(x)(CH₂)₁₋₂O(CH₂)₁₋₂OH,        —CR_(x)R_(x)NR_(x)(CH₂)₁₋₃S(O)₂OH, —CR_(x)R_(x)C(O)NR_(x)R_(x),        —NR_(x)R_(y), —NR_(x)(CH₂)₁₋₃NR_(x)R_(x), —NR_(x)C(O)(C₁₋₃        alkyl), —NR_(x)C(O)(C₁₋₃ fluoroalkyl), —NR_(x)C(O)O(C₁₋₃ alkyl),        —NR_(x)C(O)(CH₂)₁₋₃NR_(x)R_(x), —NR_(x)CH₂C(O)CH₂NR_(x)R_(x),        —C(O)(C₁₋₃ alkyl), —C(O)(CR_(x)R_(x))₁₋₃OH,        —C(O)CR_(x)R_(x)NR_(x)R_(x), —C(O)NR_(x)R_(x), —C(O)NR_(x)(C₁₋₂        cyanoalkyl), —C(O)NR_(x)(CR_(x)R_(x))₁₋₃NR_(x)R_(x),        —C(O)N(CH₂CH₃)(CR_(x)R_(x))₁₋₃NR_(x)R_(x),        —C(O)NR_(x)(CR_(x)R_(x))₁₋₂C(O)NR_(x)R_(x),        —C(O)NR_(x)(CR_(x)R_(x))₁₋₃NR_(x)C(O)(C₁₋₂ alkyl),        —O(CR_(x)R_(x))₁₋₃NR_(x)R_(x), —S(O)₂NR_(x)R_(x), or        —C(O)(CR_(x)R_(x))₁₋₂S(O)₂(C₁₋₂ alkyl);    -   (ii) 8-azabicyclo[3.2.1]octanyl, azaspiro[3.5]nonanyl,        azetidinyl, benzo[c][1,2,5]oxadiazolyl, cyclopentyl, cyclohexyl,        diazepanyl, morpholinyl, phenyl, piperazinyl, piperidinyl,        pyrazolyl, pyridinyl, pyrrolidinonyl, quinolinyl, quinuclidinyl,        tetrahydroisoquinolinyl, tetrahydropyridinyl, or thiazolidinyl,        each substituted with zero to 2 substituents independently        selected from C₁₋₄ alkyl, C₁₋₂ fluoroalkyl, C₁₋₄ hydroxyalkyl,        —NR_(x)R_(x), —(CH₂)₁₋₂NR_(x)R_(x), —C(O)(C₁₋₂ alkyl),        —C(O)CH₂NR_(x)R_(x), —C(O)O(C₁₋₃ alkyl), —CH₂C(O)NR_(x)R_(x),        C₃₋₆ cycloalkyl, —CH₂(phenyl), —CH₂(pyrrolyl),        —CH₂(morpholinyl), —CH₂(methylpiperazinyl), —CH₂(thiophenyl),        methylpiperidinyl, isobutylpiperidinyl, and pyridinyl; or    -   (iii) -L₃-R_(14c);-   each R_(14b) is F, Cl, —OH, —CH₃, or —OCH₃;-   R_(14c) is adamantanyl, azepanyl, azetidinyl, C₃₋₇ cycloalkyl,    diazepanyl, imidazolyl, indolyl, morpholinyl,    octahydropyrrolo[3,4-c]pyrrolyl, phenyl, piperazinonyl, piperazinyl,    piperidinyl, pyridinyl, pyrrolidinonyl, pyrrolidinyl, pyrrolyl,    triazolyl, or tetrazolyl, each substituted with zero to 1    substituent selected from F, —OH, C₁₋₄ alkyl, C₁₋₃ hydroxyalkyl,    —NR_(x)R_(y), —NR_(x)C(O)CH₃, —C(O)(C₁₋₂ alkyl), —C(O)NR_(x)R_(x),    —C(O)N(CH₂CH₃)₂, —C(O)(tetrahydrofuranyl), —C(O)O(C₁₋₂ alkyl),    —CH₂C(O)NR_(x)R_(y), morpholinyl, methylpiperidinyl, pyrazinyl,    pyridinyl, and pyrrolidinyl;-   L₃ is —(CR_(x)R_(x))₁₋₃—, —CH(NH₂)—, —CR_(x)R_(x)NR_(x)—, —C(O)—,    —C(O)NR_(x)(CH₂)₀₋₄—, —NR_(x)—, —NR_(x)C(O)—, —NR_(x)CH₂—,    —NR_(x)CH₂C(O)—, or —O(CH₂)₀₋₂—;-   R_(v) is H, C₁₋₂ alkyl, or C₁₋₂ fluoroalkyl;-   each R_(x) is independently H or —CH₃;-   each R_(y) is independently H or C₁₋₆ alkyl;-   n is zero, 1, or 2; and-   p is zero, 1, 2, 3, or 4.

The second aspect of the present invention provides at least onecompound of Formula (I), N-oxide, or a salt thereof, wherein:

-   G is defined in the first aspect;-   A is:-   (i) —O-L₁-R₆;-   (ii) —NR₇R₈;-   (iii) -L₂-C(O)NR₉R₁₀;-   (iv) —(CR_(x)R_(x))₁₋₃R₁₁, C₁₋₃ aminoalkyl,    —(CR_(x)R_(x))₁₋₃NR_(x)C(O)R₁₁,    —(CR_(x)R_(x))₁₋₂NR_(x)C(O)(CH₂)₁₋₂(piperidinyl),    —(CR_(x)R_(x))₁₋₂NR_(x)C(O)O(CH₂)₁₋₂(piperidinyl), or    —(CR_(x)R_(x))₁₋₂NR_(x)C(O)(CH₂)₁₋₂NR_(x)R_(x);-   (v) —CR_(x)R₁₂R₁₃, wherein R₁₂ and R₁₃ together with the carbon atom    to which they are attached form a cyclic group selected from    azabicyclo[4.1.1]octanyl, azepanyl, azetidinyl, C₃₋₇ cycloalkyl,    diazepanyl, diazaspiro[4.5]decanonyl, morpholinyl,    octahydrocyclopenta[c]pyrrolyl, piperazinyl, piperidinyl,    pyrrolidinyl, and quinuclidinyl, each substituted with zero to 4    R_(12a);-   (vi) —CR_(x)═CR_(x)(piperidinyl); or-   (vii) an aromatic group selected from    [1,2,4]triazolo[1,5-a]pyridinyl, imidazo[1,2-a]pyridinyl,    imidazolyl, indazolyl, isoquinolinyl, oxadiazolyl, oxazolyl, phenyl,    pyrazinyl, pyrazolo[3,4-b]pyridinyl, pyrazolyl, pyridazinyl,    pyridinyl, pyrimidinyl, pyrrolyl, quinolinonyl, quinolinyl,    quinoxalinyl, tetrahydro-[1,2,4]triazolo[1,5-a]pyrazinyl,    tetrahydroimidazo[1,2-a]pyrazinyl, tetrahydroisoquinolinyl,    tetrahydrothiazolo[5,4-c]pyridinyl,    tetrahydrothieno[2,3-c]pyridinyl, thiadiazolyl, thiazolyl,    thiooxadiazolyl, and triazolyl, each substituted with zero to 2    R_(14a) and zero to 3 R_(14b);-   L₁ is bond, —(CR_(x)R_(x))₁₋₂—, —(CR_(x)R_(x))₁₋₂CR_(x)(OH)—,    —(CR_(x)R_(x))₁₋₂O—, —CR_(x)R_(x)C(O)—,    —CR_(x)R_(x)C(O)NR_(x)(CR_(x)R_(x))₀₋₄—,    —CR_(x)R_(x)NR_(x)C(O)(CR_(x)R_(x))₀₋₄—, or    —CR_(x)R_(x)NR_(x)C(O)(CR_(x)R_(x))₀₋₄—;-   L₂ is a bond or —(CR_(x)R_(x))₁₋₃—;-   R₁ is H, Cl, —CN, C₁₋₄ alkyl, C₁₋₃ fluoroalkyl, C₁₋₃ hydroxyalkyl,    C₁₋₃ hydroxy-fluoroalkyl, —CR_(v)═CH₂, C₃₋₆ cycloalkyl, —CH₂(C₃₋₆    cycloalkyl), —C(O)O(C₁₋₃ alkyl), or tetrahydropyranyl;-   each R₂ is independently halo, —CN, —OH, —NO₂, C₁₋₄ alkyl, C₁₋₂    fluoroalkyl, C₁₋₂ cyanoalkyl, C₁₋₃ hydroxyalkyl, C₁₋₃ aminoalkyl,    —O(CH₂)₁₋₂OH, —(CH₂)₀₋₄O(C₁₋₄ alkyl), C₁₋₃ fluoroalkoxy,    —(CH₂)₁₋₄O(C₁₋₃ alkyl), —O(CH₂)₁₋₂OC(O)(C₁₋₃ alkyl),    —O(CH₂)₁₋₂NR_(x)R_(x), —C(O)O(C₁₋₃ alkyl), —(CH₂)₀₋₂C(O)NR_(y)R_(y),    —C(O)NR_(x)(C₁₋₅ hydroxyalkyl), —C(O)NR_(x)(C₂₋₆ alkoxyalkyl),    —C(O)NR_(x)(C₃₋₆ cycloalkyl), —NR_(y)R_(y), —NR_(y)(C₁₋₃    fluoroalkyl), —NR_(y)(C₁₋₄ hydroxyalkyl), —NR_(x)CH₂(phenyl),    —NR_(x)S(O)₂(C₃₋₆ cycloalkyl), —NR_(x)C(O)(C₁₋₃ alkyl),    —NR_(x)CH₂(C₃₋₆ cycloalkyl), —(CH₂)₀₋₂S(O)₂(C₁₋₃ alkyl),    —(CH₂)₀₋₂(C₃₋₆ cycloalkyl), —(CH₂)₀₋₂(phenyl), morpholinyl,    dioxothiomorpholinyl, dimethyl pyrazolyl, methylpiperidinyl,    methylpiperazinyl, amino-oxadiazolyl, imidazolyl, triazolyl, or    —C(O)(thiazolyl);-   R_(2a) is C₁₋₆ alkyl, C₁₋₃ fluoroalkyl, C₁₋₆ hydroxyalkyl, C₁₋₃    aminoalkyl, —(CH₂)₀₋₄O(C₁₋₃ alkyl), C₃₋₆ cycloalkyl,    —(CH₂)₁₋₃C(O)NR_(x)R_(x), —CH₂(C₃₋₆ cycloalkyl), —CH₂(phenyl),    tetrahydrofuranyl, tetrahydropyranyl, or phenyl;-   each R_(2b) is independently H, halo, —CN, —NR_(x)R_(x), C₁₋₆ alkyl,    C₁₋₃ fluoroalkyl, C₁₋₃ hydroxyalkyl, C₁₋₃ fluoroalkoxy,    —(CH₂)₀₋₂O(C₁₋₃ alkyl), —(CH₂)₀₋₃C(O)NR_(x)R_(x), —(CH₂)₁₋₃(C₃₋₆    cycloalkyl), —C(O)O(C₁₋₃ alkyl), —C(O)NR_(x)(C₁₋₃ alkyl),    —CR_(x)═CR_(x)R_(x), or —CR_(x)═CH(C₃₋₆ cycloalkyl);-   R_(2c) is R_(2a) or R_(2b);-   R_(2d) is R_(2a) or R_(2b); provided that one of R_(2c) and R_(2d)    is R_(2d), and the other of R_(2c) and R₂ is R_(2b);-   each R₅ is independently F, Cl, —CN, C₁₋₃ alkyl, C₁₋₂ fluoroalkyl,    or —OCH₃;-   R₆ is:    -   (i) —CR_(x)R_(x)C(O)NR_(x)(CR_(x)R_(x))₁₋₃OH,        —CR_(x)R_(x)C(O)NR_(x)(CR_(x)R_(x))₁₋₂NR_(x)R_(x), or        —CR_(x)R_(x)C(O)NR_(x)(CR_(x)R_(x))₁₋₂CHFCR_(x)R_(x)OH; or    -   (ii) azabicyclo[3.2.1]octanyl, azaspiro[5.5]undecanyl,        azetidinyl, C₃₋₆ cycloalkyl, diazabicyclo[2.2.1]heptanyl,        diazaspiro[3.5]nonanyl, morpholinyl, tetrahydrofuranyl,        tetrahydropyranyl, octahydrocyclopenta[c]pyrrolyl, piperazinyl,        piperidinyl, pyrrolidinyl, or quinuclidinyl, each substituted        with zero to 3 R_(6a);-   each R_(6a) is independently F, Cl, —OH, —CN, C₁₋₆ alkyl, C₁₋₄    fluoroalkyl, C₁₋₆ hydroxyalkyl, —(CH₂)₁₋₂O(C₁₋₃ alkyl),    —NR_(x)R_(x), —(CH₂)₁₋₂NR_(x)R_(x), —(CR_(x)R_(x))₁₋₂S(O)₂(C₁₋₃    alkyl), —(CR_(x)R_(x))₁₋₂C(O)NR_(x)R_(x),    —C(O)(CR_(x)R_(x))₁₋₂NR_(x)R_(x), oxetanyl, tetrahydrofuranyl,    tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl,    isobutylpiperidinyl, piperazinyl, or —O(piperidinyl);-   R₇ is:    -   (i) R_(7a), —CH₂R_(7a), —C(O)R_(7a), —C(O)CH(NH₂)R_(7a),        —C(O)(CH₂)₁₋₃NH₂, —C(O)CH(NH₂)(C₁₋₄ alkyl),        —C(O)CH(NH₂)(CH₂)₁₋₂C(O)OH, —C(O)CH(NH₂)(CH₂)₂₋₄NH₂, or        —C(O)CH(NH₂)(CH₂)₁₋₃C(O)NH₂; or    -   (ii) C₃₋₆ cycloalkyl substituted with one substituent selected        from —NR_(x)(CH₂)₂₋₃NR_(y)R_(y), —NR_(x)(methylpiperidinyl),        —NR_(x)(CH₂)₂₋₃(morpholinyl), dimethylamino piperidinyl, and        piperazinyl substituted with a substituent selected from C₁₋₄        alkyl, —C(O)CH₃, —(CH₂)₁₋₂OCH₃, —CH₂(methylphenyl),        —(CH₂)₂₋₃(pyrrolidinyl), C₃₋₆ cycloalkyl, pyridinyl, and        methylpiperidinyl;-   R_(7a) is azaspiro[3.5]nonanyl, C₃₋₆ cycloalkyl,    diazaspiro[3.5]nonanyl, diazaspiro[5.5]undecanyl, diazepanonyl,    diazepanyl, morpholinyl, phenyl, piperazinyl, piperidinyl,    pyrrolidinonyl, pyrrolidinyl, or pyrrolyl, each substituted with    zero to 1 substituent selected from C₁₋₃ alkyl, —NH₂,    methylpiperidinyl, methylpyrrolidinyl, —OCH₂CH₂(pyrrolidinyl), and    —OCH₂CH₂NHCH₂CH₃; and zero to 4 substituents selected from —CH₃;-   R_(7b) is:    -   (i) C₁₋₄ alkyl, C₁₋₃ hydroxyalkyl, —(CH₂)₂₋₃C≡CH,        —(CH₂)₁₋₂O(C₁₋₂ alkyl), —(CH₂)₁₋₂S(O)₂(C₁₋₂ alkyl),        —(CH₂)₀₋₃NR_(x)R_(y), —CH₂C(O)NR_(x)R_(x), —NR_(x)(C₁₋₄        hydroxyalkyl), —NR_(y)(C₁₋₂ cyanoalkyl), —NR_(x)(C₁₋₂        fluoroalkyl), —NR_(x)(C₂₋₄ hydroxyfluoroalkyl),        —NR_(x)(CH₂)₁₋₂C(O)NR_(x)R_(x), —NR_(x)(CH₂)₁₋₃NR_(x)R_(x),        —NR_(x)CH₂CH₂NR_(x)R_(x), —NR_(x)C(O)(CH₂)₁₋₂NR_(x)R_(x),        —O(CH₂)₁₋₃NR_(x)R_(x), —C(O)CH₂NR_(x)R_(x), —(CH₂)₁₋₂R_(7d),        —NHR_(7d), —NH(CH₂)₁₋₂R_(7d), or —OR_(7d); or    -   (ii) azepanyl, azetidinyl, diazepanyl, dioxothiomorpholinyl,        morpholinyl, oxaazaspiro[3.3]heptanyl, oxetanyl, piperazinonyl,        piperazinyl, piperidinyl, pyridinyl, pyrrolidinonyl,        pyrrolidinyl, or tetrahydroisoquinolinyl, each substituted with        zero to 1 R_(8a) and zero to 3 R_(8b);    -   each R_(7c) is independently F, Cl, —CN, C₁₋₂ alkyl, —CF₃, or        —CH₂CN;-   R_(7d) is azaspiro[3.5]nonanyl, bicyclo[1.1.1]pentanyl, C₃₋₆    cycloalkyl, morpholinyl, oxetanyl, phenyl, piperidinyl, pyrazolyl,    pyrrolidinyl, tetrahydrofuranyl, or tetrahydropyranyl, each    substituted with zero to 1 substituent selected from C₁₋₃ alkyl,    —NR_(x)R_(x), —C(O)CH₃, methylpiperidinyl, methylpyrrolidinyl,    tetramethylpiperidinyl, —OCH₂CH₂(pyrrolidinyl), and    —OCH₂CH₂NHCH₂CH₃; and zero to 4 substituents selected from —CH₃;-   R₈ is H or C₁₋₃ alkyl;-   or R₇ and R₈ together with the nitrogen atom to which they are    attached form a heterocyclic ring selected from azetidinyl,    diazepanonyl, diazepanyl, diazaspiro[3.5]nonanyl,    diazaspiro[5.5]undecanyl, imidazolyl, imidazolidinonyl,    octahydro-1H-pyrrolo[3,4-b]pyridinyl, piperazinyl, piperidinyl,    pyrrolidinonyl, pyrrolidinyl, and pyrrolyl, wherein said    heterocyclic ring is substituted with zero to 1 R_(7b) and zero to 2    Rye;-   R_(8a) is —OH, C₁₋₆ alkyl, C₁₋₄ fluoroalkyl, C₁₋₄ hydroxyalkyl,    —(CH₂)₁₋₂O(C₁₋₃ alkyl), —C(O)(C₁₋₃ alkyl), —(CH₂)₁₋₂(C₃₋₆    cycloalkyl), —(CH₂)₁₋₃(methyl phenyl), —(CH₂)₁₋₃(pyrrolidinyl),    —(CH₂)₁₋₃(methylpyrazolyl), —(CH₂)₁₋₃(thiophenyl), —NR_(x)R_(x),    C₃₋₆ cycloalkyl, methylpiperidinyl, pyridinyl, or pyrimidinyl;-   each R_(8b) is independently F, Cl, —CN, C₁₋₃ alkyl, or —CF₃;-   R₉ is C₁₋₆ alkyl, C₁₋₆ hydroxyalkyl, C₁₋₆ hydroxy fluoroalkyl, C₁₋₃    aminoalkyl, —(CH₂)₁₋₂O(C₁₋₃ alkyl), —(CH₂)₁₋₃NR_(x)R_(x),    —(CH₂)₁₋₂C(O)NR_(x)R_(x), —(CH₂)₁₋₃S(O)₂OH,    —(CR_(x)R_(x))₁₋₃NR_(x)S(O)₂(C₁₋₂ alkyl), or —(CH₂)₀₋₃R_(9a);-   R_(9a) is C₃₋₇ cycloalkyl, furanyl, phenyl, piperazinyl,    piperidinyl, pyrazolyl, pyridinyl, pyrrolidinyl, quinuclidinyl,    thiazolyl, or octahydrocyclopenta[c]pyrrolyl, each substituted with    zero to 3 substituents independently selected from F, Cl, —OH, C₁₋₄    alkyl, C₁₋₃ hydroxyalkyl, C₁₋₃ hydroxy fluoroalkyl, C₁₋₃ aminoalkyl,    —NR_(y)R_(y), oxetanyl, phenyl, piperazinyl, piperidinyl, and    pyrrolidinyl;-   R₁₀ is H, C₁₋₄ alkyl, —(CH₂)₁₋₃O(C₁₋₂ alkyl), or C₃₋₆ cycloalkyl;-   or R₉ and R₁₀ together with the nitrogen atom to which they are    attached form a heterocyclic ring selected from    azabicyclo[3.1.1]heptanyl, azaspiro[5.5]undecanyl,    diazabicyclo[2.2.1]heptanyl, diazabicyclo[3.1.1]heptanyl,    diazabicyclo[3.2.0]heptanyl, diazaspiro[3.5]nonanyl,    diazaspiro[4.4]nonanyl, diazaspiro[4.5]decanyl, diazepanyl,    indolinyl, morpholinyl, octahydropyrrolo[3,4-c]pyrrolyl,    piperazinonyl, piperazinyl, piperidinyl, and pyrrolidinyl, each    substituted with zero to 3 R_(10a);-   each R_(10a) is independently C₁₋₄ alkyl, C₁₋₄ hydroxyalkyl,    —(CH₂)₁₋₃O(C₁₋₃ alkyl), —(CH₂)₁₋₃NR_(x)R_(x),    —(CH₂)₁₋₂C(O)NR_(x)R_(x), —(CH₂)₁₋₂(methyltriazolyl),    —CH₂CH₂(phenyl), —CH₂CH₂(morpholinyl), —C(O)(C₁₋₂ alkyl),    —C(O)NR_(y)R_(y), —C(O)CH₂NR_(y)R_(y), —NR_(y)R_(y), —NHC(O)(C₁₋₃    alkyl), —C(O)(furanyl), —O(piperidinyl),    —C(O)CH₂(diethylcarbamoylpiperidinyl), methylpiperazinyl,    piperidinyl, methylpiperidinyl, diethylcarbamoylpiperidinyl,    isopropylpiperidinyl, pyridinyl, trifluoromethylpyridinyl,    pyrimidinyl, or dihydrobenzo[d]imidazolonyl;-   R₁₁ is azetidinyl, azaspiro[3.5]nonanyl, dioxidothiomorpholinyl,    hexahydropyrrolo[3,4-c]pyrrolyl, morpholinyl, piperazinyl,    piperidinyl, pyridinyl, or pyrrolidinyl, each substituted with zero    to 3 substituents independently selected from halo, —CN, C₁₋₄ alkyl,    C₁₋₃ aminoalkyl, —(CH₂)₁₋₂(phenyl), —C(O)CH₂NR_(x)R_(x), C₁₋₅    hydroxyalkyl, —(CH₂)₁₋₂C(O)NR_(x)R_(x), —(CH₂)₁₋₂S(O)₂(C₁₋₃ alkyl),    —(CH₂)₁₋₂S(O)(C₁₋₃ alkyl), oxetanyl, tetrahydrofuranyl, and    tetrahydropyranyl;-   each R_(12a) is independently F, Cl, —OH, C₁₋₆ alkyl, C₁₋₄    fluoroalkyl, C₁₋₄ cyanoalkyl, C₁₋₆ hydroxyalkyl, —(CH₂)₁₋₂O(C₁₋₃    alkyl), —(CH₂)₁₋₂C(O)NR_(x)R_(x), —(CH₂)₁₋₂S(O)₂(C₁₋₂ alkyl),    —(CH₂)₁₋₂NR_(x)HS(O)₂(C₁₋₂ alkyl), —(CH₂)₁₋₂NR_(x)R_(x), C₁₋₃    alkoxy, —NR_(y)R_(y), —NR_(x)(C₁₋₄ fluoroalkyl), —NR_(x)(C₁₋₂    cyanoalkyl), —NR_(x)CH₂NR_(x)R_(x), —NR_(x)(C₁₋₄ hydroxyalkyl),    —NR_(x)(CR_(x)R_(x)CR_(x)R_(x))O(C₁₋₃ alkyl),    —NR_(x)(CH₂C(O)NR_(x)R_(x)), —NR_(x)(C₁₋₃ alkoxy),    —NR_(x)CH₂CH₂S(O)₂(C₁₋₂ alkyl), —NR_(x)C(O)CH₃, —NR_(x)C(O)(C₁₋₂    fluoroalkyl), —NR_(x)C(O)CR_(x)R_(x)NR_(x)R_(x),    —NR_(x)C(O)CH₂NR_(y)R_(y), —NR_(x)C(O)CH₂NR_(x)(C₁₋₄ hydroxyalkyl),    —NR_(x)(CH₂)₁₋₂C(O)NR_(x)R_(x), —NR_(x)S(O)₂(C₁₋₂ alkyl), —C(O)(C₁₋₅    alkyl), —C(O)(CH₂)₁₋₃O(C₁₋₂ alkyl), —C(O)CR_(x)R_(x)NR_(y)R_(y),    R_(12b), —CR_(x)R_(x)R_(12b), —C(O)R_(12b),    —C(O)CR_(x)R_(x)NR_(x)R_(12b), —C(O)NR_(x)R_(12b),    —NR_(x)C(O)CR_(x)R_(x)R_(12b), —NR_(x)R_(12b),    —NR_(x)CR_(x)R_(x)R_(12b), —N(CH₂CN)R_(12b),    —NR_(x)C(O)CR_(x)R_(x)NR_(x)R_(12b),    —NR_(x)C(O)CR_(x)R_(x)NR_(x)CH₂R_(12b),    —NR_(x)CR_(x)R_(x)C(O)NR_(x)R_(12b), or —OR_(12b); or two R_(12a)    and the carbon atom to which they are attached form C═O;-   R_(12b) is azetidinyl, bicyclo[1.1.1]pentanyl, C₃₋₆ cycloalkyl,    diazabicyclo[2.2.1]heptanyl, dioxolanyl,    dioxidotetrahydrothiopyranyl, dioxidothiomorpholinyl, imidazolyl,    morpholinyl, octahydrocyclopenta[c]pyrrolyl,    octahydropyrrolo[3,4-c]pyrrolyl, oxaazaspiro[3.3]heptanyl, oxetanyl,    phenyl, piperazinyl, piperazinonyl, piperidinyl, pyridinyl,    pyrrolidinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydropyranyl,    or triazolyl, each substituted with zero to 4 substituents    independently selected from F, Cl, —OH, C₁₋₄ alkyl, C₁₋₃    fluoroalkyl, C₁₋₃ hydroxyalkyl, C₁₋₃ aminoalkyl, C₁₋₄ alkoxy,    —(CH₂)₁₋₂O(C₁₋₃ alkyl), —NR_(x)R_(x), —C(O)NR_(x)R_(x), and    —CR_(x)R_(x)S(O)₂(C₁₋₃ alkyl);    each R_(14a) is independently is:    -   (i) H, halo, —OH, C₁₋₆ alkyl, C₁₋₂₃ fluoroalkyl, C₁₋₄        hydroxyalkyl, —(CH₂)₀₋₂O(C₁₋₃ alkyl), —CR_(x)R_(x)NR_(y)R_(y),        —CR_(x)R_(x)NR_(x)(C₁₋₃ cyanoalkyl),        —CR_(x)R_(x)NR_(x)((CH₂)₁₋₂O(C₁₋₂ alkyl)),        —CR_(x)R_(x)N((CH₂)₁₋₂OCH₃)₂, —CR_(x)R_(x)NR_(x)(CH₂C≡CR_(x)),        —CR_(x)R_(x)NR_(x)(CH₂)₁₋₃NR_(x)R_(x),        —(CR_(x)R_(x))₁₋₃CR_(x)R_(x)NR_(x)R_(x),        —CR_(x)(NH₂)(CH₂)₁₋₄NR_(x)R_(x),        —CR_(x)R_(x)NR_(x)(CH₂)₁₋₂O(C₁₋₃ alkyl),        —CR_(x)R_(x)NR_(x)(CH₂)₁₋₂O(CH₂)₁₋₂OH,        —CR_(x)R_(x)NR_(x)(CH₂)₁₋₃S(O)₂OH, —CR_(x)R_(x)C(O)NR_(x)R_(x),        —NR_(x)R_(y), —NR_(x)(CH₂)₁₋₃NR_(x)R_(x), —NR_(x)C(O)(C₁₋₃        alkyl), —NR_(x)C(O)(C₁₋₃ fluoroalkyl), —NR_(x)C(O)O(C₁₋₃ alkyl),        —NR_(x)C(O)(CH₂)₁₋₃NR_(x)R_(x), —NR_(x)CH₂C(O)CH₂NR_(x)R_(x),        —C(O)(C₁₋₃ alkyl), —C(O)(CR_(x)R_(x))₁₋₃OH,        —C(O)CR_(x)R_(x)NR_(x)R_(x), —C(O)NR_(x)R_(x), —C(O)NR_(x)(C₁₋₂        cyanoalkyl), —C(O)NR_(x)(CR_(x)R_(x))₁₋₃NR_(x)R_(x),        —C(O)N(CH₂CH₃)(CR_(x)R_(x))₁₋₃NR_(x)R_(x),        —C(O)NR_(x)(CR_(x)R_(x))₁₋₂C(O)NR_(x)R_(x),        —C(O)NR_(x)(CR_(x)R_(x))₁₋₃NR_(x)C(O)(C₁₋₂ alkyl),        —O(CR_(x)R_(x))₁₋₃NR_(x)R_(x), —S(O)₂NR_(x)R_(x), or        —C(O)(CR_(x)R_(x))₁₋₂S(O)₂(C₁₋₂ alkyl);    -   (ii) 8-azabicyclo[3.2.1]octanyl, azaspiro[3.5]nonanyl,        azetidinyl, benzo[c][1,2,5]oxadiazolyl, cyclopentyl, cyclohexyl,        diazepanyl, morpholinyl, phenyl, piperazinyl, piperidinyl,        pyrazolyl, pyridinyl, pyrrolidinonyl, quinolinyl, quinuclidinyl,        tetrahydroisoquinolinyl, tetrahydropyridinyl, or thiazolidinyl,        each substituted with zero to 2 substituents independently        selected from C₁₋₄ alkyl, C₁₋₂ fluoroalkyl, C₁₋₄ hydroxyalkyl,        —NR_(x)R_(x), —(CH₂)₁₋₂NR_(x)R_(x), —C(O)(C₁₋₂ alkyl),        —C(O)CH₂NR_(x)R_(x), —C(O)O(C₁₋₃ alkyl), —CH₂C(O)NR_(x)R_(x),        C₃₋₆ cycloalkyl, —CH₂(phenyl), —CH₂(pyrrolyl),        —CH₂(morpholinyl), —CH₂(methylpiperazinyl), —CH₂(thiophenyl),        methylpiperidinyl, isobutylpiperidinyl, and pyridinyl; or    -   (iii) -L₃-R_(14c);-   each R_(14b) is F, Cl, —OH, —CH₃, or —OCH₃;-   R_(14c) is adamantanyl, azepanyl, azetidinyl, C₃₋₇ cycloalkyl,    diazepanyl, imidazolyl, indolyl, morpholinyl,    octahydropyrrolo[3,4-c]pyrrolyl, phenyl, piperazinonyl, piperazinyl,    piperidinyl, pyridinyl, pyrrolidinonyl, pyrrolidinyl, pyrrolyl,    triazolyl, or tetrazolyl, each substituted with zero to 1    substituent selected from F, —OH, C₁₋₄ alkyl, C₁₋₃ hydroxyalkyl,    —NR_(x)R_(y), —NR_(x)C(O)CH₃, —C(O)(C₁₋₂ alkyl), —C(O)NR_(x)R_(x),    —C(O)N(CH₂CH₃)₂, —C(O)(tetrahydrofuranyl), —C(O)O(C₁₋₂ alkyl),    —CH₂C(O)NR_(x)R_(y), morpholinyl, methylpiperidinyl, pyrazinyl,    pyridinyl, and pyrrolidinyl;-   L₃ is —(CR_(x)R_(x))₁₋₃—, —CH(NH₂)—, —CR_(x)R_(x)NR_(x)—, —C(O)—,    —C(O)NR_(x)(CH₂)₀₋₄—, —NR_(x)—, —NR_(x)C(O)—, —NR_(x)CH₂—,    —NR_(x)CH₂C(O)—, or —O(CH₂)₀₋₂—;-   R_(v) is H, C₁₋₂ alkyl, or C₁₋₂ fluoroalkyl;-   each R_(x) is independently H or —CH₃;-   each R_(y) is independently H or C₁₋₆ alkyl;-   n is zero, 1, or 2; and-   p is zero, 1, 2, 3, or 4.

The compounds of Formula (I) or salts thereof in which A is—CR_(x)R₁₂R₁₃; and R₁₂ and R₁₃ together with the carbon atom to whichthey are attached form a cyclic group and the cyclic group has one ormore heteroatoms, the cyclic group is bonded to the indole ring by acarbon atom in the cyclic group.

One embodiment provides a compound of Formula (I) or a salt thereofwherein G is

and A, R₁, R₅, and n are defined in the first aspect or the secondaspect.

One embodiment provides a compound of Formula (I), N-oxide, or a saltthereof wherein G is:

and A, R₁, R₂, R₅, n, and p are defined in the first aspect or thesecond aspect.

One embodiment provides a compound of Formula (I) or a salt thereofwherein G is

and A, R₁, R_(2a), R_(2b), R_(2c), R_(2d), R₅, n, and p are defined inthe first aspect or the second aspect. Included in this embodiment arecompounds in which R_(2a) is C₁₋₄ alkyl, C₁₋₂ fluoroalkyl, C₁₋₄hydroxyalkyl, —(CH₂)₁₋₃OCH₃, C₃₋₆ cycloalkyl, —CH₂C(O)NR_(x)R_(x),—CH₂(C₃₋₆ cycloalkyl), —CH₂(phenyl), tetrahydrofuranyl, or phenyl; andeach R_(2b) is independently H, F, Cl, —CN, —NR_(x)R_(x), C₁₋₆ alkyl,C₁₋₂ fluoroalkyl, C₁₋₃ hydroxyalkyl, —(CH₂)₀₋₂O(C₁₋₂ alkyl),—(CH₂)₀₋₂C(O)NR_(x)R_(x), —(CH₂)₁₋₃(cyclopropyl), —C(O)O(C₁₋₂ alkyl),—C(O)NR_(x)(C₁₋₃ alkyl), —CR_(x)═CH₂, or —CH═CH(C₃₋₆ cycloalkyl). Alsoincluded in this embodiment are compounds in which R_(2a) is —CH₃; andeach R_(2b) is independently H, Cl, or —CH₃.

One embodiment provides a compound of Formula (I), or a salt thereofwherein G is a 9-membered heterocyclic ring selected from:

and A, R₁, R₂, R₅, n, and p are defined in the first aspect or thesecond aspect.

One embodiment provides a compound of Formula (I) or a salt thereofwherein G is a 10-membered heterocyclic ring selected from:

and A, R₁, R₂, R₅, n, and p are defined in the first aspect or thesecond aspect.

One embodiment provides a compound of Formula (I), N-oxide, or a saltthereof,

wherein:

-   A is:-   (i) —O-L₁-R₆;-   (ii) —NR₇R₈;-   (iii) -L₂-C(O)NR₉R₁₀;-   (iv) —(CR_(x)R_(x))₁₋₂R₁₁, C₁₋₂ aminoalkyl,    —(CR_(x)R_(x))₁₋₂NR_(x)C(O)R₁₁, —CH₂NR_(x)C(O)(CH₂)₁₋₂(piperidinyl),    —CH₂NR_(x)C(O)OCH₂(piperidinyl), or    —CH₂NR_(x)C(O)(CH₂)₁₋₂NR_(x)R_(x);-   (v) —CR_(x)R₁₂R₁₃, wherein R₁₂ and R₁₃ together with the carbon atom    to which they are attached form a cyclic group selected from    azabicyclo[4.1.1]octanyl, azepanyl, azetidinyl, C₃₋₇ cycloalkyl,    diazepanyl, diazaspiro[4.5]decanonyl, morpholinyl,    octahydrocyclopenta[c]pyrrolyl, piperazinyl, piperidinyl,    pyrrolidinyl, and quinuclidinyl, each substituted with zero to 3    R_(12a);-   (vi) —CR_(x)CR_(x)(piperidinyl); or-   (vii) an aromatic group selected from    [1,2,4]triazolo[1,5-a]pyridinyl, imidazo[1,2-a]pyridinyl,    imidazolyl, indazolyl, isoquinolinyl, oxadiazolyl, oxazolyl, phenyl,    pyrazinyl, pyrazolo[3,4-b]pyridinyl, pyrazolyl, pyridazinyl,    pyridinyl, pyrimidinyl, pyrrolyl, quinolinonyl, quinolinyl,    quinoxalinyl, tetrahydro-[1,2,4]triazolo[1,5-a]pyrazinyl,    tetrahydroimidazo[1,2-a]pyrazinyl, tetrahydroisoquinolinyl,    tetrahydrothiazolo[5,4-c]pyridinyl,    tetrahydrothieno[2,3-c]pyridinyl, thiadiazolyl, thiazolyl,    thiooxadiazolyl, and triazolyl, each substituted with zero to 2    R_(14a) and zero to 3 R_(14b);-   L₁ is bond, —(CR_(x)R_(x))₁₋₂—, —CH₂C(O)—,    —CH₂C(O)NR_(x)(CR_(x)R_(x))₀₋₂—, —CH₂NR_(x)C(O)—, or    —CH₂NR_(x)C(O)CH₂—;-   L₂ is a bond or —(CR_(x)R_(x))₁₋₂—;-   R₁ is H, Cl, —CN, C₁₋₄ alkyl, C₁₋₂ fluoroalkyl, C₁₋₂ hydroxyalkyl,    or —C(O)O(C₁₋₂ alkyl); each R₂ is independently F, Cl, —CN, —OH,    C₁₋₃ alkyl, C₁₋₂ fluoroalkyl, C₁₋₂ cyanoalkyl, C₁₋₃ hydroxyalkyl,    C₁₋₂ aminoalkyl, —(CH₂)₀₋₂O(C₁₋₃ alkyl), C₃₋₆ cycloalkyl,    —NR_(x)R_(x), —(CH₂)₀₋₂C(O)NR_(x)R_(x), —(CH₂)₀₋₂S(O)₂(C₁₋₃ alkyl),    —CH₂(C₃₋₆ cycloalkyl), —CH₂(phenyl), or phenyl;-   R_(2a) is C₁₋₄ alkyl, C₁₋₂ fluoroalkyl, C₁₋₄ hydroxyalkyl,    —(CH₂)₁₋₃OCH₃, C₃₋₆ cycloalkyl, —CH₂C(O)NR_(x)R_(x), —CH₂(C₃₋₆    cycloalkyl), —CH₂(phenyl), tetrahydrofuranyl, or phenyl;-   each R_(2b) is independently H, F, Cl, —CN, —NR_(x)R_(x), C₁₋₆    alkyl, C₁₋₂ fluoroalkyl, C₁₋₃ hydroxyalkyl, —(CH₂)₀₋₂O(C₁₋₂ alkyl),    —(CH₂)₀₋₂C(O)NR_(x)R_(x), —(CH₂)₁₋₃(cyclopropyl), —C(O)O(C₁₋₂    alkyl), —C(O)NR_(x)(C₁₋₃ alkyl), —CR_(x)═CH₂, or —CH═CH(C₃₋₆    cycloalkyl);-   each R₅ is independently F, Cl, —CN, C₁₋₂ alkyl, or —OCH₃; R₆ is:    -   (i) —CH₂C(O)NHCH₂CR_(x)R_(x)OH, —CH₂C(O)NHCH₂CH₂CR_(x)R_(x)OH,        —CH₂C(O)NHCH₂CH₂NR_(x)R_(x), or —CH₂C(O)NHCH₂CHFCR_(x)R_(x)OH;        or    -   (ii) azabicyclo[3.2.1]octanyl, azaspiro[5.5]undecanyl,        azetidinyl, C₃₋₆ cycloalkyl, diazabicyclo[2.2.1]heptanyl,        diazaspiro[3.5]nonanyl, morpholinyl, tetrahydropyranyl,        octahydrocyclopenta[c]pyrrolyl, piperazinyl, piperidinyl,        pyrrolidinyl, or quinuclidinyl, each substituted with zero to 3        R_(6a);-   each R_(6a) is independently F, —OH, C₁₋₄ alkyl, C₁₋₄ fluoroalkyl,    C₁₋₄ hydroxyalkyl, —(CH₂)₁₋₂OCH₃, —NR_(x)R_(x),    —(CH₂)₁₋₂NR_(x)R_(x), —(CH₂)₁₋₂S(O)₂(C₁₋₂ alkyl),    —(CH₂)₁₋₂C(O)NR_(x)R_(x), —C(O)CH₂NR_(x)R_(x), oxetanyl,    tetrahydrofuranyl, tetrahydropyranyl, piperidinyl,    isobutylpiperidinyl, piperazinyl, or —O(piperidinyl);-   R₇ is:    -   (i) R_(7a), —CH₂R_(7a), —C(O)R_(7a), —C(O)CH(NH₂)R_(7a),        —C(O)(CH₂)₁₋₃NH₂, —C(O)CH(NH₂)(C₁₋₄ alkyl),        —C(O)CH(NH₂)(CH₂)₁₋₂C(O)OH, —C(O)CH(NH₂)(CH₂)₂₋₄NH₂, or        —C(O)CH(NH₂)(CH₂)₁₋₃C(O)NH₂; or    -   (ii) C₃₋₆ cycloalkyl substituted with one substituent selected        from —NR_(x)(CH₂)₂₋₃NR_(x)R_(x), —NH(CH₂)₂₋₃NHCH₃,        —NH(methylpiperidinyl), —NH(CH₂)₂₋₃(morpholinyl), dimethylamino        piperidinyl, and piperazinyl substituted with a substituent        selected from C₁₋₄ alkyl, —C(O)CH₃, —(CH₂)₁₋₂OCH₃,        —CH₂(methylphenyl), —(CH₂)₂₋₃(pyrrolidinyl), C₃₋₆ cycloalkyl,        pyridinyl, and methylpiperidinyl;-   R_(7b) is:    -   (i) C₁₋₄ alkyl, C₁₋₂ fluoroalkyl, C₁₋₂ cyanoalkyl, C₁₋₄        hydroxyalkyl, —(CH₂)₂₋₃C≡CH, —(CH₂)₁₋₂O(C₁₋₂ alkyl),        —(CH₂)₁₋₂S(O)₂(C₁₋₂ alkyl), —(CH₂)₀₋₃NR_(x)R_(y),        —CH₂C(O)NR_(x)R_(x), —NR_(x)(C₁₋₄ hydroxyalkyl),        —NR_(x)(CR_(x)R_(x))₁₋₂O(C₁₋₂ alkyl), —NR_(y)(C₁₋₂ cyanoalkyl),        —NR_(x)(C₁₋₂ fluoroalkyl), —NR_(x)(C₂₋₅ hydroxyfluoroalkyl),        —NR_(x)(CH₂)₁₋₂C(O)NR_(x)R_(x), —NR_(x)(CH₂)₁₋₃NR_(x)R_(x),        —NR_(x)CH₂CH₂NR_(x)R_(x), —NR_(x)C(O)(CH₂)₁₋₂NR_(x)R_(x),        —O(CH₂)₁₋₃NR_(x)R_(x), —C(O)(C₁₋₃ alkyl), —C(O)CH₂NR_(x)R_(x),        —S(O)₂(C₁₋₂ alkyl), —(CH₂)₁₋₂R_(7d), —CR_(x)R_(x)C(O)R_(7d),        —C(O)CR_(x)R_(x)R_(7d), —NHR_(7d), —NH(CH₂)₁₋₂R_(7d), or        —OR_(7d); or    -   (ii) azepanyl, azetidinyl, bicyclo[1.1.1]pentanyl, C₃₋₆        cycloalkyl, diazepanyl, dioxothiomorpholinyl, morpholinyl,        oxaazaspiro[3.3]heptanyl, oxetanyl, piperazinonyl, piperazinyl,        piperidinyl, pyridinyl, pyrrolidinonyl, pyrrolidinyl,        tetrahydrofuranyl, tetrahydroisoquinolinyl, or        tetrahydropyranyl, each substituted with zero to 1 R_(8a) and        zero to 3 R_(8b);-   each Rye is independently F, —CH₃ or —CH₂CN;-   R_(7a) is azaspiro[3.5]nonanyl, bicyclo[1.1.1]pentanyl, C₃₋₆    cycloalkyl, morpholinyl, oxetanyl, phenyl, piperidinyl, pyrazolyl,    pyrrolidinyl, tetrahydrofuranyl, or tetrahydropyranyl, each    substituted with zero to 1 substituent selected from C₁₋₃ alkyl,    —NH₂, —C(O)CH₃, methylpiperidinyl, methylpyrrolidinyl,    tetramethylpiperidinyl, —OCH₂CH₂(pyrrolidinyl), and    —OCH₂CH₂NHCH₂CH₃; and zero to 4 substituents selected from —CH₃;-   R₈ is H or C₁₋₂ alkyl;-   or R₇ and R₈ together with the nitrogen atom to which they are    attached form a heterocyclic ring selected from azetidinyl,    diazepanonyl, diazepanyl, diazaspiro[3.3]heptanyl,    diazaspiro[3.5]nonanyl, diazaspiro[5.5]undecanyl, imidazolyl,    imidazolidinonyl, octahydro-1H-pyrrolo[3,4-b]pyridinyl, piperazinyl,    piperidinyl, pyrrolidinonyl, pyrrolidinyl, and pyrrolyl, wherein    said heterocyclic ring is substituted with zero to 1 R_(7b) and zero    to 2 R_(7c);-   R_(8a) is —OH, C₁₋₄ alkyl, C₁₋₃ fluoroalkyl, —(CH₂)₁₋₂O(C₁₋₂ alkyl),    —C(O)(C₁₋₂ alkyl), —CH₂(C₃₋₆ cycloalkyl), —(CH₂)₁₋₂(methyl phenyl),    —(CH₂)₁₋₃(pyrrolidinyl), —(CH₂)₁₋₂(methylpyrazolyl),    —(CH₂)₁₋₂(thiophenyl), —NR_(x)R_(x), C₃₋₆ cycloalkyl,    methylpiperidinyl, or pyridinyl;-   each R_(8b) is independently F or —CH₃;-   R₉ is C₁₋₃ alkyl, C₁₋₅ hydroxyalkyl, C₂₋₅ hydroxy fluoroalkyl, C₁₋₂    aminoalkyl, —(CH₂)₁₋₂O(C₁₋₂ alkyl), —(CH₂)₁₋₃N(CH₃)₂,    —(CH₂)₁₋₂C(O)NH₂, —(CH₂)₁₋₂S(O)₂OH, —(CH₂)₁₋₂CR_(x)R_(x)NHS(O)₂CH₃,    or —(CH₂)₀₋₃R_(9a);-   R_(9a) is C₅₋₇ cycloalkyl, furanyl, phenyl, piperazinyl,    piperidinyl, pyrazolyl, pyridinyl, pyrrolidinyl, quinuclidinyl,    thiazolyl, or octahydrocyclopenta[c]pyrrolyl, each substituted with    zero to 2 substituents independently selected from —OH, C₁₋₃ alkyl,    —NR_(x)R_(x), oxetanyl, phenyl, piperazinyl, piperidinyl, and    pyrrolidinyl;-   R₁₀ is H, C₁₋₃ alkyl, —(CH₂)₁₋₂O(C₁₋₂ alkyl), or C₃₋₆ cycloalkyl;-   or R₉ and R₁₀ together with the nitrogen atom to which they are    attached form a heterocyclic ring selected from    azabicyclo[3.1.1]heptanyl, azaspiro[5.5]undecanyl,    diazabicyclo[2.2.1]heptanyl, diazabicyclo[3.1.1]heptanyl,    diazabicyclo[3.2.0]heptanyl, diazaspiro[3.5]nonanyl,    diazaspiro[4.4]nonanyl, diazaspiro[4.5]decanyl, diazepanyl,    indolinyl, morpholinyl, octahydropyrrolo[3,4-c]pyrrolyl,    piperazinonyl, piperazinyl, piperidinyl, and pyrrolidinyl, each    substituted with zero to 3 R_(10a);-   each R_(10a) is independently C₁₋₃ alkyl, C₁₋₃ hydroxyalkyl,    —(CH₂)₁₋₂O(C₁₋₂ alkyl), —(CH₂)₁₋₂NR_(x)R_(x), —CH₂C(O)NR_(x)R_(x),    —CH₂(methyltriazolyl), —CH₂CH₂(phenyl), —CH₂CH₂(morpholinyl),    —C(O)(C₁₋₂ alkyl), —C(O)NH₂, —C(O)N(C₁₋₂ alkyl)₂,    —C(O)CH₂NR_(x)R_(x), —NR_(x)R_(x), —NHC(O)(C₁₋₂ alkyl),    —C(O)(furanyl), —O(piperidinyl),    —C(O)CH₂(diethylcarbamoylpiperidinyl), methylpiperazinyl,    piperidinyl, methylpiperidinyl, diethylcarbamoylpiperidinyl,    isopropylpiperidinyl, pyridinyl, trifluoromethylpyridinyl,    pyrimidinyl, or dihydrobenzo[d]imidazolonyl;-   R₁₁ is azetidinyl, azaspiro[3.5]nonanyl, dioxidothiomorpholinyl,    hexahydropyrrolo[3,4-c]pyrrolyl, morpholinyl, piperazinyl,    piperidinyl, pyridinyl, or pyrrolidinyl, each substituted with zero    to 3 substituents independently selected from F, Cl, —CN, C₁₋₃    alkyl, C₁₋₂ aminoalkyl, —CH₂(phenyl), —C(O)CH₂NR_(x)R_(x),    —CH₂CR_(x)R_(x)OH, —CH₂C(O)NR_(x)R_(x), —CH₂CH₂S(O)₂(C₁₋₃ alkyl),    —CH₂CH₂S(O)(C₁₋₃ alkyl), oxetanyl, tetrahydrofuranyl, and    tetrahydropyranyl;-   each R_(12a) is independently —OH, C₁₋₄ alkyl, C₁₋₃ fluoroalkyl,    C₁₋₂ cyanoalkyl, C₁₋₄ hydroxyalkyl, —(CH₂)₁₋₂O(C₁₋₂ alkyl),    —CH₂C(O)NR_(x)R_(x), —(CH₂)₁₋₂S(O)₂(C₁₋₂ alkyl),    —(CH₂)₁₋₂NHS(O)₂(C₁₋₂ alkyl), —(CH₂)₁₋₂NR_(x)R_(x), C₁₋₂ alkoxy,    —NR_(y)R_(y), —NR_(x)(C₁₋₃ fluoroalkyl), —NR_(x)(C₂₋₅    hydroxyfluoroalkyl), —NR_(x)(CH₂CR_(x)R_(x))OCH₃, —NR_(x)(C₁₋₂    cyanoalkyl), —NR_(x)CH₂NR_(x)R_(x), —NR_(x)(C₁₋₄ hydroxyalkyl),    —NR_(x)(CH₂C(O)NH₂), —NR_(x)(OCH₃), —NR_(x)CH₂CH₂S(O)₂(C₁₋₂ alkyl),    —NR_(x)(CH₂CR_(x)R_(x)OCH₃), —NR_(x)C(O)CH₃, —NR_(x)C(O)(C₁₋₄    fluoroalkyl), —NR_(x)C(O)CR_(x)R_(x)NR_(x)R_(x),    —NR_(x)C(O)CH₂NR_(y)R_(y), —NR_(x)C(O)CH₂NR_(x)(C₁₋₄ hydroxyalkyl),    —NR_(x)CH₂C(O)NR_(x)R_(x), —NR_(x)S(O)₂CH₃, —C(O)(C₁₋₅ alkyl),    —C(O)CH₂O(C₁₋₂ alkyl), —C(O)CH₂CH₂O(C₁₋₂ alkyl),    —C(O)CH₂NR_(x)R_(x), —C(O)CHR_(x)NR_(y)R_(y), R_(12b),    —CR_(x)R_(x)R_(12b), —C(O)R_(12b), —C(O)CH₂NR_(x)R_(12b),    —C(O)NR_(x)R_(12b), —NR_(x)C(O)CR_(x)R_(x)R_(12b), —NR_(x)R_(12b),    —N(CH₂CN)R_(12b), —NR_(x)CR_(x)R_(x)R_(12b),    —NR_(x)C(O)CH₂NR_(x)R_(12b), —NR_(x)C(O)CH₂NR_(x)CH₂R_(12b),    —NR_(x)CH₂C(O)NR_(x)R_(12b), or —OR_(12b); or two R_(12a) and the    carbon atom to which they are attached form C═O;-   R_(12b) is azetidinyl, bicyclo[1.1.1]pentanyl, C₃₋₆ cycloalkyl,    diazabicyclo[2.2.1]heptanyl, dioxolanyl,    dioxidotetrahydrothiopyranyl, dioxidothiomorpholinyl, imidazolyl,    morpholinyl, octahydrocyclopenta[c]pyrrolyl,    octahydropyrrolo[3,4-c]pyrrolyl, oxaazaspiro[3.3]heptanyl, oxetanyl,    phenyl, piperazinyl, piperazinonyl, piperidinyl, pyridinyl,    pyrrolidinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydropyranyl,    or triazolyl, each substituted with zero to 4 substituents    independently selected from F, Cl, —OH, C₁₋₃ alkyl, C₁₋₂    hydroxyalkyl, C₁₋₂ alkoxy, —(CH₂)₁₋₂O(C₁₋₂ alkyl), —NR_(x)R_(x),    —C(O)NR_(x)R_(x), and —CH₂S(O)₂(C₁₋₂ alkyl);-   each R_(14a) is independently:    -   (i) H, F, Cl, —OH, C₁₋₅ alkyl, C₁₋₂ fluoroalkyl, C₁₋₂        hydroxyalkyl, —(CH₂)₀₋₂OCH₃, —CHR_(x)NR_(x)(C₁₋₅ alkyl),        —CHR_(x)NR_(x)(C₁₋₂ cyanoalkyl), —CHR_(x)NR_(x)((CH₂)₁₋₂OCH₃),        —CHR_(x)N((CH₂)₁₋₂OCH₃)₂, —CH₂NR_(x)(CH₂C≡CR_(x)),        —CH₂NR_(x)CH₂CH₂NR_(x)R_(x), —(CH₂)₁₋₃CR_(x)R_(x)NR_(x)R_(x),        —CH(NH₂)(CH₂)₃₋₄NR_(x)R_(x), —CH₂NR_(x)(CH₂)₁₋₂O(C₁₋₃ alkyl),        —CH₂NR_(x)(CH₂)₁₋₂O(CH₂)₁₋₂OH, —CH₂NH(CH₂)₁₋₂S(O)₂OH,        —CH₂C(O)NR_(x)R_(x), —NR_(x)R_(y), —NR_(x)(CH₂)₂₋₃NR_(x)R_(x),        —NR_(x)C(O)(C₁₋₂ alkyl), —NR_(x)C(O)(C₁₋₂ fluoroalkyl),        —NR_(x)C(O)O(C₁₋₃ alkyl), —NR_(x)C(O)(CH₂)₁₋₂NR_(x)R_(x),        —NR_(x)CH₂C(O)CH₂NR_(x)R_(x), —C(O)(C₁₋₂ alkyl),        —C(O)CH₂CR_(x)R_(x)OH, —C(O)CH₂NR_(x)R_(x), —C(O)NR_(x)R_(x),        —C(O)NR_(x)(CH₂CN), —C(O)NR_(x)(CR_(x)R_(x))₂₋₃NR_(x)R_(x),        —C(O)N(CH₂CH₃)(CR_(x)R_(x))₂₋₃NR_(x)R_(x),        —C(O)NR_(x)CH₂C(O)NR_(x)R_(x), —C(O)NR_(x)CH₂CH₂NR_(x)C(O)CH₃,        —O(CR_(x)R_(x))₂₋₃NR_(x)R_(x), —S(O)₂NR_(x)R_(x), or        —C(O)CH₂S(O)₂(C₁₋₂ alkyl);    -   (ii) 8-azabicyclo[3.2.1]octanyl, azaspiro[3.5]nonanyl,        azetidinyl, benzo[c][1,2,5]oxadiazolyl, cyclopentyl, cyclohexyl,        diazepanyl, morpholinyl, phenyl, piperazinyl, piperidinyl,        pyrazolyl, pyridinyl, pyrrolidinonyl, quinolinyl, quinuclidinyl,        tetrahydroisoquinolinyl, tetrahydropyridinyl, or thiazolidinyl,        each substituted with zero to 2 substituents independently        selected from C₁₋₄ alkyl, C₁₋₂ fluoroalkyl, C₁₋₄ hydroxyalkyl,        —NR_(x)R_(x), —(CH₂)₁₋₂NR_(x)R_(x), —C(O)(C₁₋₂ alkyl),        —C(O)CH₂NR_(x)R_(x), —C(O)O(C₁₋₃ alkyl), —CH₂C(O)NR_(x)R_(x),        C₃₋₆ cycloalkyl, —CH₂(phenyl), —CH₂(pyrrolyl),        —CH₂(morpholinyl), —CH₂(methylpiperazinyl), —CH₂(thiophenyl),        methylpiperidinyl, isobutylpiperidinyl, and pyridinyl; or (iii)        -L₃-R_(14c);-   each R_(14b) is F, —CH₃, or —OCH₃;-   L₃ is —(CR_(x)R_(x))₁₋₃—, —CH(NH₂)—, —CR_(x)R_(x)NH—, —C(O)—,    —C(O)NR_(x)(CH₂)₀₋₄—, —NR_(x)—, —NR_(x)C(O)—, —NR_(x)CH₂—,    —NR_(x)CH₂C(O)—, —O—, or —O(CH₂)₁₋₂—; and-   R_(14c) is adamantanyl, azetidinyl, C₃₋₆ cycloalkyl, diazepanyl,    imidazolyl, indolyl, morpholinyl, octahydropyrrolo[3,4-c]pyrrolyl,    phenyl, piperazinonyl, piperazinyl, piperidinyl, pyridinyl,    pyrrolidinonyl, pyrrolidinyl, or tetrazolyl, each substituted with    zero to 1 substituent selected from F, —OH, C₁₋₄ alkyl, C₁₋₃    hydroxyalkyl, —NR_(x)R_(y), —NR_(x)C(O)CH₃, —C(O)(C₁₋₂ alkyl),    —C(O)NR_(x)R_(x), —C(O)N(CH₂CH₃)₂, —C(O)(tetrahydrofuranyl),    —C(O)O(C₁₋₂ alkyl), —CH₂C(O)NR_(x)R_(y), morpholinyl,    methylpiperidinyl, pyrazinyl, pyridinyl, and pyrrolidinyl;-   and G is defined in the first aspect or the second aspect.

One embodiment provides a compound of Formula (I), N-oxide, or a saltthereof, wherein:

-   A is:-   (i) —O-L₁-R₆;-   (ii) —NR₇R₈;-   (iii) -L₂-C(O)NR₉R₁₀;-   (iv) —(CR_(x)R_(x))₁₋₂R₁₁, C₁₋₂ aminoalkyl,    —(CR_(x)R_(x))₁₋₂NR_(x)C(O)R₁₁, —CH₂NR_(x)C(O)(CH₂)₁₋₂(piperidinyl),    —CH₂NR_(x)C(O)OCH₂(piperidinyl), or    —CH₂NR_(x)C(O)(CH₂)₁₋₂NR_(x)R_(x);-   (v) —CR_(x)R₁₂R₁₃, wherein R₁₂ and R₁₃ together with the carbon atom    to which they are attached form a cyclic group selected from    azabicyclo[4.1.1]octanyl, azepanyl, azetidinyl, C₃₋₇ cycloalkyl,    diazepanyl, diazaspiro[4.5]decanonyl, morpholinyl,    octahydrocyclopenta[c]pyrrolyl, piperazinyl, piperidinyl,    pyrrolidinyl, and quinuclidinyl, each substituted with zero to 3    R_(12a);-   (vi) —CR_(x)═CR_(x)(piperidinyl); or-   (vii) an aromatic group selected from    [1,2,4]triazolo[1,5-a]pyridinyl, imidazo[1,2-a]pyridinyl,    imidazolyl, indazolyl, isoquinolinyl, oxadiazolyl, oxazolyl, phenyl,    pyrazinyl, pyrazolo[3,4-b]pyridinyl, pyrazolyl, pyridazinyl,    pyridinyl, pyrimidinyl, pyrrolyl, quinolinonyl, quinolinyl,    quinoxalinyl, tetrahydro-[1,2,4]triazolo[1,5-a]pyrazinyl,    tetrahydroimidazo[1,2-a]pyrazinyl, tetrahydroisoquinolinyl,    tetrahydrothiazolo[5,4-c]pyridinyl,    tetrahydrothieno[2,3-c]pyridinyl, thiadiazolyl, thiazolyl,    thiooxadiazolyl, and triazolyl, each substituted with zero to 2    R_(14a) and zero to 3 R_(14b);-   L₁ is bond, —(CR_(x)R_(x))₁₋₂—, —CH₂C(O)—,    —CH₂C(O)NR_(x)(CR_(x)R_(x))₀₋₂—, —CH₂NR_(x)C(O)—, or    —CH₂NR_(x)C(O)CH₂—;-   L₂ is a bond or —(CR_(x)R_(x))₁₋₂—;-   R₁ is H, Cl, —CN, C₁₋₄ alkyl, C₁₋₂ fluoroalkyl, C₁₋₂ hydroxyalkyl,    or —C(O)O(C₁₋₂ alkyl);-   each R₂ is independently F, Cl, —CN, —OH, C₁₋₃ alkyl, C₁₋₂    fluoroalkyl, C₁₋₂ cyanoalkyl, C₁₋₃ hydroxyalkyl, C₁₋₂ aminoalkyl,    —(CH₂)₀₋₂O(C₁₋₃ alkyl), C₃₋₆ cycloalkyl, —NR_(x)R_(x),    —(CH₂)₀₋₂C(O)NR_(x)R_(x), —(CH₂)₀₋₂S(O)₂(C₁₋₃ alkyl), —CH₂(C₃₋₆    cycloalkyl), —CH₂(phenyl), or phenyl;-   R_(2a) is C₁₋₄ alkyl, C₁₋₂ fluoroalkyl, C₁₋₄ hydroxyalkyl,    —(CH₂)₁₋₃OCH₃, C₃₋₆ cycloalkyl, —CH₂C(O)NR_(x)R_(x), —CH₂(C₃₋₆    cycloalkyl), —CH₂(phenyl), tetrahydrofuranyl, or phenyl;-   each R_(2b) is independently H, F, Cl, —CN, —NR_(x)R_(x), C₁₋₆    alkyl, C₁₋₂ fluoroalkyl, C₁₋₃ hydroxyalkyl, —(CH₂)₀₋₂O(C₁₋₂ alkyl),    —(CH₂)₀₋₂C(O)NR_(x)R_(x), —(CH₂)₁₋₃(cyclopropyl), —C(O)O(C₁₋₂    alkyl), —C(O)NR_(x)(C₁₋₃ alkyl), —CR_(x)═CH₂, or —CH═CH(C₃₋₆    cycloalkyl);-   each R₅ is independently F, Cl, —CN, C₁₋₂ alkyl, or —OCH₃;-   R₆ is:    -   (i) —CH₂C(O)NHCH₂CR_(x)R_(x)OH, —CH₂C(O)NHCH₂CH₂CR_(x)R_(x)OH,        —CH₂C(O)NHCH₂CH₂NR_(x)R_(x), or —CH₂C(O)NHCH₂CHFCR_(x)R_(x)OH;        or    -   (ii) azabicyclo[3.2.1]octanyl, azaspiro[5.5]undecanyl,        azetidinyl, C₃₋₆ cycloalkyl, diazabicyclo[2.2.1]heptanyl,        diazaspiro[3.5]nonanyl, morpholinyl, tetrahydropyranyl,        octahydrocyclopenta[c]pyrrolyl, piperazinyl, piperidinyl,        pyrrolidinyl, or quinuclidinyl, each substituted with zero to 3        R_(6a);-   each R_(6a) is independently F, —OH, C₁₋₄ alkyl, C₁₋₄ fluoroalkyl,    C₁₋₄ hydroxyalkyl, —(CH₂)₁₋₂OCH₃, —NR_(x)R_(x),    —(CH₂)₁₋₂NR_(x)R_(x), —(CH₂)₁₋₂S(O)₂(C₁₋₂ alkyl),    —(CH₂)₁₋₂C(O)NR_(x)R_(x), —C(O)CH₂NR_(x)R_(x), oxetanyl,    tetrahydrofuranyl, tetrahydropyranyl, piperidinyl,    isobutylpiperidinyl, piperazinyl, or —O(piperidinyl);-   R₇ is:    -   (i) R_(7a), —CH₂R_(7a), —C(O)R_(7a), —C(O)CH(NH₂)R_(7a),        —C(O)(CH₂)₁₋₃NH₂, —C(O)CH(NH₂)(C₁₋₄ alkyl),        —C(O)CH(NH₂)(CH₂)₁₋₂C(O)OH, —C(O)CH(NH₂)(CH₂)₂₋₄NH₂, or        —C(O)CH(NH₂)(CH₂)₁₋₃C(O)NH₂; or    -   (ii) C₃₋₆ cycloalkyl substituted with one substituent selected        from —NR_(x)(CH₂)₂₋₃NR_(x)R_(x), —NH(CH₂)₂₋₃NHCH₃,        —NH(methylpiperidinyl), —NH(CH₂)₂₋₃(morpholinyl), dimethylamino        piperidinyl, and piperazinyl substituted with a substituent        selected from C₁₋₄ alkyl, —C(O)CH₃, —(CH₂)₁₋₂OCH₃,        —CH₂(methylphenyl), —(CH₂)₂₋₃(pyrrolidinyl), C₃₋₆ cycloalkyl,        pyridinyl, and methylpiperidinyl;-   R_(7b) is:    -   (i) C₁₋₄ alkyl, C₁₋₃ hydroxyalkyl, —(CH₂)₂₋₃C≡CH,        —(CH₂)₁₋₂O(C₁₋₂ alkyl), —(CH₂)₁₋₂S(O)₂(C₁₋₂ alkyl),        —(CH₂)₀₋₃NR_(x)R_(y), —CH₂C(O)NR_(x)R_(x), —NR_(x)(C₁₋₄        hydroxyalkyl), —NR_(y)(C₁₋₂ cyanoalkyl), —NR_(x)(C₁₋₂        fluoroalkyl), —NR_(x)(C₂₋₄ hydroxyfluoroalkyl),        —NR_(x)(CH₂)₁₋₂C(O)NR_(x)R_(x), —NR_(x)(CH₂)₁₋₃NR_(x)R_(x),        —NR_(x)CH₂CH₂NR_(x)R_(x), —NR_(x)C(O)(CH₂)₁₋₂NR_(x)R_(x),        —O(CH₂)₁₋₃NR_(x)R_(x), —C(O)CH₂NR_(x)R_(x), —(CH₂)₁₋₂R_(7d),        —NHR_(7d), —NH(CH₂)₁₋₂R_(7d), or —OR_(7d); or    -   (ii) azepanyl, azetidinyl, diazepanyl, dioxothiomorpholinyl,        morpholinyl, oxaazaspiro[3.3]heptanyl, oxetanyl, piperazinonyl,        piperazinyl, piperidinyl, pyridinyl, pyrrolidinonyl,        pyrrolidinyl, or tetrahydroisoquinolinyl, each substituted with        zero to 1 R_(8a) and zero to 3 R_(8b);-   each R_(7c) is independently F, —CH₃ or —CH₂CN;-   R_(7d) is azaspiro[3.5]nonanyl, bicyclo[1.1.1]pentanyl, C₃₋₆    cycloalkyl, morpholinyl, oxetanyl, phenyl, piperidinyl, pyrazolyl,    pyrrolidinyl, tetrahydrofuranyl, or tetrahydropyranyl, each    substituted with zero to 1 substituent selected from C₁₋₃ alkyl,    —NH₂, —C(O)CH₃, methylpiperidinyl, methylpyrrolidinyl,    tetramethylpiperidinyl, —OCH₂CH₂(pyrrolidinyl), and    —OCH₂CH₂NHCH₂CH₃; and zero to 4 substituents selected from —CH₃;-   R₈ is H or C₁₋₂ alkyl;-   or R₇ and R₈ together with the nitrogen atom to which they are    attached form a heterocyclic ring selected from azetidinyl,    diazepanonyl, diazepanyl, diazaspiro[3.5]nonanyl,    diazaspiro[5.5]undecanyl, imidazolyl, imidazolidinonyl,    octahydro-1H-pyrrolo[3,4-b]pyridinyl, piperazinyl, piperidinyl,    pyrrolidinonyl, pyrrolidinyl, and pyrrolyl, wherein said    heterocyclic ring is substituted with zero to 1 R_(7b) and zero to 2    R_(7c);-   R_(8a) is —OH, C₁₋₄ alkyl, C₁₋₃ fluoroalkyl, —(CH₂)₁₋₂O(C₁₋₂ alkyl),    —C(O)(C₁₋₂ alkyl), —CH₂(C₃₋₆ cycloalkyl), —(CH₂)₁₋₂(methyl phenyl),    —(CH₂)₁₋₃(pyrrolidinyl), —(CH₂)₁₋₂(methylpyrazolyl),    —(CH₂)₁₋₂(thiophenyl), —NR_(x)R_(x), C₃₋₆ cycloalkyl,    methylpiperidinyl, or pyridinyl;-   each R_(8b) is independently F or —CH₃;-   R₉ is C₁₋₃ alkyl, C₁₋₅ hydroxyalkyl, C₂₋₅ hydroxy fluoroalkyl, C₁₋₂    aminoalkyl, —(CH₂)₁₋₂O(C₁₋₂ alkyl), —(CH₂)₁₋₃N(CH₃)₂,    —(CH₂)₁₋₂C(O)NH₂, —(CH₂)₁₋₂S(O)₂OH, —(CH₂)₁₋₂CR_(x)R_(x)NHS(O)₂CH₃,    or —(CH₂)₀₋₃R_(9a);-   R_(9a) is C₅₋₇ cycloalkyl, furanyl, phenyl, piperazinyl,    piperidinyl, pyrazolyl, pyridinyl, pyrrolidinyl, quinuclidinyl,    thiazolyl, or octahydrocyclopenta[c]pyrrolyl, each substituted with    zero to 2 substituents independently selected from —OH, C₁₋₃ alkyl,    —NR_(x)R_(x), oxetanyl, phenyl, piperazinyl, piperidinyl, and    pyrrolidinyl;-   R₁₀ is H, C₁₋₃ alkyl, —(CH₂)₁₋₂O(C₁₋₂ alkyl), or C₃₋₆ cycloalkyl;-   or R₉ and R₁₀ together with the nitrogen atom to which they are    attached form a heterocyclic ring selected from    azabicyclo[3.1.1]heptanyl, azaspiro[5.5]undecanyl,    diazabicyclo[2.2.1]heptanyl, diazabicyclo[3.1.1]heptanyl,    diazabicyclo[3.2.0]heptanyl, diazaspiro[3.5]nonanyl,    diazaspiro[4.4]nonanyl, diazaspiro[4.5]decanyl, diazepanyl,    indolinyl, morpholinyl, octahydropyrrolo[3,4-c]pyrrolyl,    piperazinonyl, piperazinyl, piperidinyl, and pyrrolidinyl, each    substituted with zero to 3 R_(10a);-   each R_(10a) is independently C₁₋₃ alkyl, C₁₋₃ hydroxyalkyl,    —(CH₂)₁₋₂O(C₁₋₂ alkyl), —(CH₂)₁₋₂NR_(x)R_(x), —CH₂C(O)NR_(x)R_(x),    —CH₂(methyltriazolyl), —CH₂CH₂(phenyl), —CH₂CH₂(morpholinyl),    —C(O)(C₁₋₂ alkyl), —C(O)NH₂, —C(O)N(C₁₋₂ alkyl)₂,    —C(O)CH₂NR_(x)R_(x), —NR_(x)R_(x), —NHC(O)(C₁₋₂ alkyl),    —C(O)(furanyl), —O(piperidinyl),    —C(O)CH₂(diethylcarbamoylpiperidinyl), methylpiperazinyl,    piperidinyl, methylpiperidinyl, diethylcarbamoylpiperidinyl,    isopropylpiperidinyl, pyridinyl, trifluoromethylpyridinyl,    pyrimidinyl, or dihydrobenzo[d]imidazolonyl; Rn is azetidinyl,    azaspiro[3.5]nonanyl, dioxidothiomorpholinyl,    hexahydropyrrolo[3,4-c]pyrrolyl, morpholinyl, piperazinyl,    piperidinyl, pyridinyl, or pyrrolidinyl, each substituted with zero    to 3 substituents independently selected from F, Cl, —CN, C₁₋₃    alkyl, C₁₋₂ aminoalkyl, —CH₂(phenyl), —C(O)CH₂NR_(x)R_(x),    —CH₂CR_(x)R_(x)OH, —CH₂C(O)NR_(x)R_(x), —CH₂CH₂S(O)₂(C₁₋₃ alkyl),    —CH₂CH₂S(O)(C₁₋₃ alkyl), oxetanyl, tetrahydrofuranyl, and    tetrahydropyranyl;-   each R_(12a) is independently —OH, C₁₋₄ alkyl, C₁₋₃ fluoroalkyl,    C₁₋₂ cyanoalkyl, C₁₋₄ hydroxyalkyl, —(CH₂)₁₋₂O(C₁₋₂ alkyl),    —CH₂C(O)NR_(x)R_(x), —(CH₂)₁₋₂S(O)₂(C₁₋₂ alkyl),    —(CH₂)₁₋₂NHS(O)₂(C₁₋₂ alkyl), —(CH₂)₁₋₂NR_(x)R_(x), C₁₋₂ alkoxy,    —NR_(y)R_(y), —NR_(x)(C₁₋₃ fluoroalkyl),    —NR_(x)(CH₂CR_(x)R_(x))OCH₃, —NR_(x)(C₁₋₂ cyanoalkyl),    —NR_(x)CH₂NR_(x)R_(x), —NR_(x)(C₁₋₄ hydroxyalkyl),    —NR_(x)(CH₂C(O)NH₂), —NR_(x)(OCH₃), —NR_(x)CH₂CH₂S(O)₂(C₁₋₂ alkyl),    —NR_(x)C(O)CH₃, —NR_(x)C(O)(C₁₋₄ fluoroalkyl),    —NR_(x)C(O)CR_(x)R_(x)NR_(x)R_(x), —NR_(x)C(O)CH₂NR_(y)R_(y),    —NR_(x)C(O)CH₂NR_(x)(C₁₋₄ hydroxyalkyl), —NR_(x)CH₂C(O)NR_(x)R_(x),    —NR_(x)S(O)₂CH₃, —C(O)(C₁₋₅ alkyl), —C(O)CH₂O(C₁₋₂ alkyl),    —C(O)CH₂CH₂O(C₁₋₂ alkyl), —C(O)CH₂NR_(x)R_(x),    —C(O)CHR_(x)NR_(y)R_(y), R_(12b), —CR_(x)R_(x)R_(12b), —C(O)R_(12b),    —C(O)CH₂NR_(x)R_(12b), —C(O)NR_(x)R_(12b),    —NR_(x)C(O)CR_(x)R_(x)R_(12b), —NR_(x)R_(12b),    —NR_(x)CR_(x)R_(x)R_(12b), —N(CH₂CN)R_(12b),    —NR_(x)C(O)CH₂NR_(x)R_(12b), —NR_(x)C(O)CH₂NR_(x)CH₂R_(12b),    —NR_(x)CH₂C(O)NR_(x)R_(12b), or —OR_(12b); or two R_(12a) and the    carbon atom to which they are attached form C═O;-   R_(12b) is azetidinyl, bicyclo[1.1.1]pentanyl, C₃₋₆ cycloalkyl,    diazabicyclo[2.2.1]heptanyl, dioxolanyl,    dioxidotetrahydrothiopyranyl, dioxidothiomorpholinyl, imidazolyl,    morpholinyl, octahydrocyclopenta[c]pyrrolyl,    octahydropyrrolo[3,4-c]pyrrolyl, oxaazaspiro[3.3]heptanyl, oxetanyl,    phenyl, piperazinyl, piperazinonyl, piperidinyl, pyridinyl,    pyrrolidinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydropyranyl,    or triazolyl, each substituted with zero to 4 substituents    independently selected from F, Cl, —OH, C₁₋₃ alkyl, C₁₋₂    hydroxyalkyl, C₁₋₂ alkoxy, —(CH₂)₁₋₂O(C₁₋₂ alkyl), —NR_(x)R_(x),    —C(O)NR_(x)R_(x), and —CH₂S(O)₂(C₁₋₂ alkyl);-   each R_(14a) is independently:    -   (i) H, F, Cl, —OH, C₁₋₅ alkyl, C₁₋₂ fluoroalkyl, C₁₋₂        hydroxyalkyl, —(CH₂)₀₋₂OCH₃, —CHR_(x)NR_(x)(C₁₋₅ alkyl),        —CHR_(x)NR_(x)(C₁₋₂ cyanoalkyl), —CHR_(x)NR_(x)((CH₂)₁₋₂OCH₃),        —CHR_(x)N((CH₂)₁₋₂OCH₃)₂, —CH₂NR_(x)(CH₂C≡CR_(x)),        —CH₂NR_(x)CH₂CH₂NR_(x)R_(x), —(CH₂)₁₋₃CR_(x)R_(x)NR_(x)R_(x),        —CH(NH₂)(CH₂)₃₋₄NR_(x)R_(x), —CH₂NR_(x)(CH₂)₁₋₂O(C₁₋₃ alkyl),        —CH₂NR_(x)(CH₂)₁₋₂O(CH₂)₁₋₂OH, —CH₂NH(CH₂)₁₋₂S(O)₂OH,        —CH₂C(O)NR_(x)R_(x), —NR_(x)R_(y), —NR_(x)(CH₂)₂₋₃NR_(x)R_(x),        —NR_(x)C(O)(C₁₋₂ alkyl), —NR_(x)C(O)(C₁₋₂ fluoroalkyl),        —NR_(x)C(O)O(C₁₋₃ alkyl), —NR_(x)C(O)(CH₂)₁₋₂NR_(x)R_(x),        —NR_(x)CH₂C(O)CH₂NR_(x)R_(x), —C(O)(C₁₋₂ alkyl),        —C(O)CH₂CR_(x)R_(x)OH, —C(O)CH₂NR_(x)R_(x), —C(O)NR_(x)R_(x),        —C(O)NR_(x)(CH₂CN), —C(O)NR_(x)(CR_(x)R_(x))₂₋₃NR_(x)R_(x),        —C(O)N(CH₂CH₃)(CR_(x)R_(x))₂₋₃NR_(x)R_(x),        —C(O)NR_(x)CH₂C(O)NR_(x)R_(x), —C(O)NR_(x)CH₂CH₂NR_(x)C(O)CH₃,        —O(CR_(x)R_(x))₂₋₃NR_(x)R_(x), —S(O)₂NR_(x)R_(x), or        —C(O)CH₂S(O)₂(C₁₋₂ alkyl);    -   (ii) 8-azabicyclo[3.2.1]octanyl, azaspiro[3.5]nonanyl,        azetidinyl, benzo[c][1,2,5]oxadiazolyl, cyclopentyl, cyclohexyl,        diazepanyl, morpholinyl, phenyl, piperazinyl, piperidinyl,        pyrazolyl, pyridinyl, pyrrolidinonyl, quinolinyl, quinuclidinyl,        tetrahydroisoquinolinyl, tetrahydropyridinyl, or thiazolidinyl,        each substituted with zero to 2 substituents independently        selected from C₁₋₄ alkyl, C₁₋₂ fluoroalkyl, C₁₋₄ hydroxyalkyl,        —NR_(x)R_(x), —(CH₂)₁₋₂NR_(x)R_(x), —C(O)(C₁₋₂ alkyl),        —C(O)CH₂NR_(x)R_(x), —C(O)O(C₁₋₃ alkyl), —CH₂C(O)NR_(x)R_(x),        C₃₋₆ cycloalkyl, —CH₂(phenyl), —CH₂(pyrrolyl),        —CH₂(morpholinyl), —CH₂(methylpiperazinyl), —CH₂(thiophenyl),        methylpiperidinyl, isobutylpiperidinyl, and pyridinyl; or    -   (iii) -L₃-R_(14c);-   each R_(14b) is F, —CH₃, or —OCH₃;-   L₃ is —(CR_(x)R_(x))₁₋₃—, —CH(NH₂)—, —CR_(x)R_(x)NH—, —C(O)—,    —C(O)NR_(x)(CH₂)₀₋₄—, —NR_(x)—, —NR_(x)C(O)—, —NR_(x)CH₂—,    —NR_(x)CH₂C(O)—, —O—, or —O(CH₂)₁₋₂—; and-   R_(14c) is adamantanyl, azetidinyl, C₃₋₆ cycloalkyl, diazepanyl,    imidazolyl, indolyl, morpholinyl, octahydropyrrolo[3,4-c]pyrrolyl,    phenyl, piperazinonyl, piperazinyl, piperidinyl, pyridinyl,    pyrrolidinonyl, pyrrolidinyl, or tetrazolyl, each substituted with    zero to 1 substituent selected from F, —OH, C₁₋₄ alkyl, C₁₋₃    hydroxyalkyl, —NR_(x)R_(y), —NR_(x)C(O)CH₃, —C(O)(C₁₋₂ alkyl),    —C(O)NR_(x)R_(x), —C(O)N(CH₂CH₃)₂, —C(O)(tetrahydrofuranyl),    —C(O)O(C₁₋₂ alkyl), —CH₂C(O)NR_(x)R_(y), morpholinyl,    methylpiperidinyl, pyrazinyl, pyridinyl, and pyrrolidinyl.    and G, n, and p is defined in the first aspect or the second aspect.

One embodiment provides a compound of Formula (I), N-oxide, or a saltthereof, wherein:

-   A is:-   (i) —O-L₁-R₆;-   (ii) —NR₇R₈;-   (iii) -L₂-C(O)NR₉R₁₀;-   (iv) —CHR_(x)R₁₁, —CH₂CH₂R₁₁, —CH₂NH₂, —CH₂NHC(O)R₁₁,    —CH₂NHC(O)CH₂CH₂(piperidinyl), —CH₂NHC(O)OCH₂(piperidinyl), or    —CH₂NHC(O)CH₂CH₂N(CH₃)₂;-   (v) —CHR₁₂R₁₃, wherein R₁₂ and R₁₃ together with the carbon atom to    which they are attached form a cyclic group selected from    azabicyclo[4.1.1]octanyl, azepanyl, azetidinyl, C₃₋₆ cycloalkyl,    diazaspiro[4.5]decanonyl, morpholinyl,    octahydrocyclopenta[c]pyrrolyl, piperidinyl, pyrrolidinyl, and    quinuclidinyl, each substituted with zero to 3 R_(12a);-   (vi) —CH═CH(piperidinyl); or-   (vii) an aromatic group selected from    [1,2,4]triazolo[1,5-a]pyridinyl, imidazo[1,2-a]pyridinyl,    imidazolyl, indazolyl, isoquinolinyl, oxadiazolyl, oxazolyl, phenyl,    pyrazinyl, pyrazolo[3,4-b]pyridinyl, pyrazolyl, pyridazinyl,    pyridinyl, pyrimidinyl, pyrrolyl, quinolinonyl, quinolinyl,    quinoxalinyl, tetrahydro-[1,2,4]triazolo[1,5-a]pyrazinyl,    tetrahydroimidazo[1,2-a]pyrazinyl, tetrahydroisoquinolinyl,    tetrahydrothiazolo[5,4-c]pyridinyl,    tetrahydrothieno[2,3-c]pyridinyl, thiadiazolyl, thiazolyl,    thiooxadiazolyl, and triazolyl, each substituted with zero to 2    R_(14a) and zero to 3 R_(14b);-   L₁ is bond, —CH₂—, —CH₂CH₂—, —CH₂C(O)—, —CH₂C(O)NH—,    —CH₂C(O)N(CH₃)—, —CH₂C(O)NHCH₂—, or —CH₂C(O)NHCH₂CH₂—;-   L₂ is a bond, —CH(CH₃)—, —C(CH₃)₂—, or —CH₂CH₂—;-   R₆ is:    -   (i) —CH₂C(O)NHCH₂C(CH₃)₂OH, —CH₂C(O)NHCH₂CH₂C(CH₃)₂OH,        —CH₂C(O)NHCH₂CH₂NH₂, or —CH₂C(O)NHCH₂CHFC(CH₃)₂OH; or    -   (ii) azabicyclo[3.2.1]octanyl, azaspiro[5.5]undecanyl,        azetidinyl, cyclohexyl, diazabicyclo[2.2.1]heptanyl,        diazaspiro[3.5]nonanyl, morpholinyl,        octahydrocyclopenta[c]pyrrolyl, piperazinyl, piperidinyl,        pyrrolidinyl, or quinuclidinyl, each substituted with zero to 2        R_(6a);-   each R_(6a) is independently F, —OH, —CH₃, —CH₂CH₂CH₃, —C(CH₃)₂,    —CH₂CH(CH₃)₂, —CH₂CH₂CH₂CF₃, —CH₂CH₂OH, —CH₂CH₂CH₂OH, —CH₂CH(CH₃)OH,    —CH₂C(CH₃)₂OH, —CH₂CH₂OCH₃, —NH₂, —N(CH₃)₂, —CH₂NH₂, —CH₂CH₂NH₂,    —CH₂CH₂S(O)₂CH₃, —CH₂C(O)N(CH₃)₂, —C(O)CH₂N(CH₃)₂, oxetanyl,    tetrahydropyranyl, piperidinyl, isobutylpiperidinyl, or    —O(piperidinyl);-   R₇ is:    -   (i) —CH₂(isopropyl azaspiro[3.5]nonanyl),        —CH₂(methylpyrrolidinyl), —C(O)(CH₂)₁₋₃NH₂,        —C(O)CH(NH₂)CH₂CH₂CH₃, —C(O)CH(NH₂)CH₂CH(CH₃)₂,        —C(O)CH(NH₂)CH(CH₃)CH₂CH₃, —C(O)CH(NH₂)CH₂CH₂C(O)OH,        —C(O)CH(NH₂)(CH₂)₃₋₄NH₂, —C(O)CH(NH₂)(CH₂)₁₋₂C(O)NH₂,        —C(O)CH(NH₂)(cyclohexyl), —C(O)CH(NH₂)(phenyl),        —C(O)(aminocyclohexyl), —C(O)(morpholinyl), —C(O)(pyrrolidinyl),        pentamethylpiperidinyl, methylpiperidinyl-piperidinyl,        methylpyrrolidinyl-pyrrolidinyl, or phenyl substituted with        —OCH₂CH₂(pyrrolidinyl) or —OCH₂CH₂NHCH₂CH₃; or    -   (ii) cyclohexyl substituted with —NR_(x)(CH₂)₂₋₃N(CH₃)₂,        —NHCH₂CH₂NHCH₃, —NH(methylpiperidinyl),        —NH(CH₂)₂₋₃(morpholinyl), dimethylamino piperidinyl, or        piperazinyl substituted with —CH₃, —CH₂CH₃, —C(CH₃)₃,        —CH₂CH(CH₃)₂, —C(O)CH₃, —CH₂CH₂OCH₃, —CH₂(methylphenyl),        —(CH₂)₂₋₃(pyrrolidinyl), cyclopentyl, pyridinyl, or        methylpiperidinyl;-   R_(7b) is:    -   (i) C₁₋₄ alkyl, C₁₋₂ fluoroalkyl, C₁₋₂ cyanoalkyl, C₃₋₄        hydroxyalkyl, —CH₂CH₂CH₂C≡CH, —CH₂CH₂OCH₃, —CH₂CH₂S(O)₂CH₃,        —(CH₂)₁₋₂NR_(x)R_(x), —CH₂C(O)NR_(x)R_(x), —NR_(x)R_(y),        —NR_(x)(C₁₋₄ hydroxyalkyl), —NR_(x)(CH₂CR_(x)R_(x)OCH₃),        —NR_(y)(C₁₋₂ cyanoalkyl), —NR_(x)(C₁₋₂ fluoroalkyl),        —NR_(x)(C₂₋₅ hydroxyfluoroalkyl),        —NR_(x)(CH₂)₁₋₂C(O)NR_(x)R_(x), —NR_(x)(CH₂)₁₋₃NR_(x)R_(x),        —NR_(x)CH₂CH₂N(CH₃)₂, —NR_(x)C(O)(CH₂)₁₋₂NR_(x)R_(x),        —OCH₂CH₂N(CH₃)₂, —C(O)(C₁₋₃ alkyl), —C(O)CH₂NR_(x)R_(x),        —S(O)₂CH₃, —(CH₂)₁₋₂R_(7d), —CH₂C(O)R_(7d), —C(O)CH₂R_(7d),        —NHR_(7d), —NH(CH₂)₁₋₂R_(7d), or —OR_(7d); or    -   (ii) azepanyl, azetidinyl, bicyclo[1.1.1]pentanyl, C₄₋₆        cycloalkyl, diazepanyl, dioxothiomorpholinyl, morpholinyl,        oxaazaspiro[3.3]heptanyl, oxetanyl, piperazinonyl, piperazinyl,        piperidinyl, pyridinyl, pyrrolidinonyl, pyrrolidinyl,        tetrahydrofuranyl, tetrahydroisoquinolinyl, or        tetrahydropyranyl, each substituted with zero to 1 R_(8a) and        zero to 3 R_(8b);-   each R_(7c) is independently —CH₃ or —CH₂CN;-   R_(7d) is azaspiro[3.5]nonanyl, bicyclo[1.1.1]pentanyl, C₃₋₆    cycloalkyl, morpholinyl, oxetanyl, phenyl, piperidinyl, pyrazolyl,    pyrrolidinyl, tetrahydrofuranyl, or tetrahydropyranyl, each    substituted with zero to 1 substituent selected from C₁₋₃ alkyl,    —NH₂, —C(O)CH₃, methylpiperidinyl, methylpyrrolidinyl,    tetramethylpiperidinyl, —OCH₂CH₂(pyrrolidinyl), and    —OCH₂CH₂NHCH₂CH₃; and zero to 4 substituents selected from —CH₃;-   R₈ is H, —CH₃ or —CH₂CH₃;-   or R₇ and R₈ together with the nitrogen atom to which they are    attached form a heterocyclic ring selected from azetidinyl,    diazepanonyl, diazepanyl, diazaspiro[3.3]heptanyl,    diazaspiro[3.3]heptanyl, diazaspiro[3.5]nonanyl,    diazaspiro[5.5]undecanyl, imidazolidinonyl,    octahydro-1H-pyrrolo[3,4-b]pyridinyl, piperazinyl, piperidinyl,    pyrrolidinonyl, and pyrrolidinyl, wherein said heterocyclic ring is    substituted with zero to 1 R_(7b) and zero to 2 R_(7c);-   R_(8a) is —OH, —CH₃, —CH₂CH₃, —CH(CH₃)₂, —C(CH₃)₃, —CH₂CH(CH₃)₂,    —CH₂CH₂OCH₃, —CH₂CH₂CF₃, —C(O)CH₃, —CH₂(cyclopropyl), —CH₂(methyl    phenyl), —(CH₂)₂₋₃(pyrrolidinyl), —CH₂(methylpyrazolyl),    —CH₂(thiophenyl), —NR_(x)R_(x), cyclopentyl, methylpiperidinyl, or    pyridinyl;-   each R_(8b) is —CH₃;-   R₉ is —CH₃, —CH₂CH₂OH, —CH₂C(CH₃)₂OH, —CH₂C(CH₃)₂CH₂OH,    —CH₂CHFC(CH₃)₂OH, —CH₂CH₂C(CH₃)₂OH, —CH(CH₂OH)₂, —CH₂CH₂OCH₃,    —CH₂CH₂NH₂, —CH₂CH₂N(CH₃)₂, —CH₂CH₂CH₂N(CH₃)₂, —CH₂CH₂C(O)NH₂,    —CH₂S(O)₂OH, —CH₂CH₂C(CH₃)₂NHS(O)₂CH₃, or —(CH₂)₀₋₃R_(9a); R_(9a) is    cyclohexyl, cycloheptyl, furanyl, phenyl, piperazinyl, piperidinyl,    pyrazolyl, pyridinyl, pyrrolidinyl, quinuclidinyl, thiazolyl, or    octahydrocyclopenta[c]pyrrolyl, each substituted with zero to 2    substituents independently selected from —OH, C₁₋₃ alkyl, —NH₂,    —N(CH₃)₂, oxetanyl, phenyl, piperazinyl, piperidinyl, and    pyrrolidinyl;-   R₁₀ is H, —CH₃, —CH₂CH₃, —CH₂CH₂OCH₃, or cyclopropyl;-   or R₉ and R₁₀ together with the nitrogen atom to which they are    attached form a heterocyclic ring selected from    azabicyclo[3.1.1]heptanyl, azaspiro[5.5]undecanyl,    diazabicyclo[2.2.1]heptanyl, diazabicyclo[3.1.1]heptanyl,    diazabicyclo[3.2.0]heptanyl, diazaspiro[3.5]nonanyl,    diazaspiro[4.4]nonanyl, diazaspiro[4.5]decanyl, diazepanyl,    indolinyl, morpholinyl, octahydropyrrolo[3,4-c]pyrrolyl,    piperazinonyl, piperazinyl, piperidinyl, and pyrrolidinyl, each    substituted with zero to 2 R_(10a);-   each R_(10a) is independently —CH₃, —CH₂CH₃, —CH(CH₃)₂, —CH₂OH,    —CH₂CH₂OH, —CH₂OCH₃, —CH₂CH₂OCH₃, —CH₂NH₂, —CH₂CH₂NH₂,    —CH₂CH₂NH(CH₃), —CH₂C(O)NH(CH₃), —CH₂C(O)N(CH₃)₂,    —CH₂(methyltriazolyl), —CH₂CH₂(phenyl), —CH₂CH₂(morpholinyl),    —C(O)CH₃, —C(O)NH₂, —C(O)N(CH₂CH₃)₂, —C(O)CH₂NH(CH₃),    —C(O)CH₂N(CH₃)₂, —NH₂, —N(CH₃)₂, —NHC(O)CH₃, —C(O)(furanyl),    —O(piperidinyl), —C(O)CH₂(diethylcarbamoylpiperidinyl),    methylpiperazinyl, piperidinyl, methylpiperidinyl,    diethylcarbamoylpiperidinyl, isopropylpiperidinyl, pyridinyl,    trifluoromethylpyridinyl, pyrimidinyl, or    dihydrobenzol[d]imidazolonyl; Rn is azetidinyl,    azaspiro[3.5]nonanyl, dioxidothiomorpholinyl,    hexahydropyrrolo[3,4-c]pyrrolyl, morpholinyl, piperazinyl,    piperidinyl, or pyrrolidinyl, each substituted with zero to 2    substituents independently selected from F, —CH₃, —CH(CH₃)₂, —CH₂CN,    —CH₂(phenyl), —C(O)CH₂N(CH₃)₂, —CH₂C(CH₃)₂OH, —CH₂C(O)N(CH₃)₂,    —CH₂CH₂S(O)₂CH₃, —CH₂CH₂S(O)CH₃, oxetanyl, and tetrahydropyranyl;-   each R_(12a) is independently —OH, —CH₃, —CH₂CH₂CH₃, —CH(CH₃)₂,    —CH₂CH(CH₃)₂, —CF₃, —CH₂CF₃, —CH₂CH₂CH₂CF₃, —CH₂CN, —CH₂C(CH₃)₂OH,    —CH₂CH₂OCH₃, —CH₂C(O)NH(CH₃), —CH₂C(O)N(CH₃)₂, —CH₂C(O)NH₂,    —CH₂CH₂S(O)₂CH₃, —CH₂CH₂NHS(O)₂CH₃, —CH₂NR_(x)R_(x), —CH₂CH₂NH(CH₃),    —OCH₃, —NR_(x)R_(y), —NR_(x)(C₂₋₄ fluoroalkyl),    —NR_(x)(CH₂CHFC(CH₃)₂OH), —NR_(x)(CH₂CR_(x)R_(x)OCH₃), —NH(CH₂CN),    —N(CH₃)CH₂N(CH₃)₂, —NR_(x)(CH₂CHFC(CH₃)₂OH), —NH(CH₂CH₂OCH₃),    —NH(CH₂C(CH₃)₂OH), —NR_(x)(CH₂C(O)NR_(x)R_(x)), —N(CH₃)(OCH₃),    —NR_(x)CH₂CH₂S(O)₂CH₃, —NHC(O)CH₃, —NHC(O)CH₂CF₃,    —NHC(O)CHR_(x)NH(CH₃), —NR_(x)C(O)CH₂N(CH₃)₂,    —NHC(O)CH₂N(CH₃)(CH₂CH₃), —NHC(O)CH₂N(CH₂CH₃)₂,    —NHC(O)CH₂NH(CH₂C(CH₃)₂OH), —NHCH₂C(O)NR_(x)(CH₃), —NHS(O)₂CH₃,    —C(O)C(CH₃)₃, —C(O)CH(CH₂CH₃)₂, —C(O)CH₂OCH₃, —C(O)CH₂CH₂OCH₃,    —C(O)CH₂NH(CH₃), —C(O)CH₂N(CH₃)₂, —C(O)CH(CH₃)NH(CH₃),    —C(O)CH₂N(CH₃)(CH₂CH₃), —C(O)CH₂N(CH₂CH₃)₂, R_(12b), —CH₂R_(12b),    —C(O)R_(12b), —C(O)CH₂R_(12b), —C(O)CH₂NHR_(12b),    —C(O)NR_(x)R_(12b), —NR_(x)C(O)CH₂R_(12b), —NR_(x)R_(12b),    —N(CH₂CN)R_(12b), —NR_(x)CH₂R_(12b), —N(CH₂CN)R_(12b),    —NHC(O)CH₂NR_(x)R_(12b), —NHC(O)CH₂NR_(x)CH₂R_(12b),    —NHCH₂C(O)NHR_(12b), or —OR_(12b); or two R_(12a) and the carbon    atom to which they are attached form C═O;-   R_(12b) is azetidinyl, bicyclo[1.1.1]pentanyl, cyclopropyl,    diazabicyclo[2.2.1]heptanyl, dioxolanyl,    dioxidotetrahydrothiopyranyl, dioxidothiomorpholinyl, imidazolyl,    morpholinyl, octahydrocyclopenta[c]pyrrolyl,    octahydropyrrolo[3,4-c]pyrrolyl, oxaazaspiro[3.3]heptanyl, oxetanyl,    phenyl, piperazinyl, piperazinonyl, piperidinyl, pyridinyl,    pyrrolidinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydropyranyl,    or triazolyl, each substituted with zero to 4 substituents    independently selected from F, —OH, —CH₃, —CH(CH₃)₂, —CH₂OH, —OCH₃,    —CH₂CH₂OCH₃, —NR_(x)R_(x), —C(O)NH₂, and —CH₂S(O)₂CH₃;-   each R_(14a) is independently:    -   (i) H, F, Cl, —OH, —CH₃, —CH(CH₃)₂, —CH(CH₃)(CH₂CH₃),        —CH₂CH₂CH₂C(CH₃)₂, —CF₃, —CH₂CF₃, —CH₂OH, —OCH₃, —CH₂CH₂OCH₃,        —CHR_(x)NR_(x)(CH₃), —CH₂N(CH₃)(CH(CH₃)₂), —CH₂NH(CH₂C(CH₃)₃),        —CH₂NH(CH₂CN), —CH₂N(CH₃)(CH₂CH₂OCH₃), —CH₂N(CH₂CH₂OCH₃)₂,        —CH₂NR_(x)(CH₂C≡CH), —CH₂NHCH₂CH₂N(CH₃)₂, —CH₂CH₂NR_(x)(CH₃),        —CH₂CR_(x)(CH₃)NH₂, —CH₂CH₂CH₂N(CH₃)₂, —CH₂CH₂CH₂CH₂NH₂,        —CH(NH₂)(CH₂)₃₋₄NH₂, —CH₂NHCH₂CH₂O(C₁₋₃ alkyl),        —CH₂NHCH₂CH₂OCH₂CH₂OH, —CH₂NHCH₂CH₂S(O)₂OH, —CH₂C(O)NR_(x)(CH₃),        —NR_(x)R_(x), —NH(CH(CH₃)₂), —NHCH₂CH₂NH(CH₃),        —NHCH₂CH₂CH₂N(CH₃)₂, —NHC(O)CH₃, —NHC(O)CF₃, —NHC(O)OC(CH₃)₃,        —NHC(O)CH₂N(CH₃)₂, —NHC(O)CH₂CH₂N(CH₃)₂, —NHCH₂C(O)CH₂NH(CH₃),        —C(O)CH₃, —C(O)CH₂CH(CH₃)OH, —C(O)CH₂NR_(x)(CH₃),        —C(O)NR_(x)R_(x), —C(O)NH(CH₂CN), —C(O)NHCH₂CH₂CH₂NR_(x)R_(x),        —C(O)NHCH₂CH(CH₃)CH₂NH₂, —C(O)NHCH₂C(O)NH₂,        —C(O)N(CH₃)CH₂CH₂CH₂N(CH₃)₂, —C(O)N(CH₂CH₃)CH₂CH₂N(CH₃)₂,        —OCH₂CH₂CH₂N(CH₃)₂, —C(O)NHCH₂CH₂NHC(O)CH₃, —S(O)₂NH₂, or        —C(O)CH₂S(O)₂CH₃;    -   (ii) 8-azabicyclo[3.2.1]octanyl, azaspiro[3.5]nonanyl,        azetidinyl, benzo[c][1,2,5]oxadiazolyl, cyclopentyl, cyclohexyl,        diazepanyl, morpholinyl, phenyl, piperazinyl, piperidinyl,        pyrazolyl, pyridinyl, pyrrolidinonyl, quinolinyl, quinuclidinyl,        tetrahydroisoquinolinyl, tetrahydropyridinyl, or thiazolidinyl,        each substituted with zero to 2 substituents independently        selected from —CH₃, —CH(CH₃)₂, —CH₂CH(CH₃)₂, —CF₃, —CH₂CH₂CF₃,        —CH₂CH₂OH, —CH₂CH₂CH(CH₃)OH, —NH₂, —CH₂N(CH₃)₂, —CH₂CH₂NH(CH₃),        —C(O)CH₃, —C(O)CH₂NH(CH₃), —C(O)CH₂N(CH₃)₂, —C(O)O(C(CH₃)₃),        —CH₂C(O)NR_(x)(CH₃), cyclobutyl, cyclopentyl, —CH₂(phenyl),        —CH₂(pyrrolyl), —CH₂(morpholinyl), —CH₂(methylpiperazinyl),        —CH₂(thiophenyl), methylpiperidinyl, isobutylpiperidinyl, and        pyridinyl; or    -   (iii) -L₃-R_(14c);    -   each R_(14b) is —CH₃;-   L₃ is —(CH₂)₁₋₃—, —CH(CH₃)—, —CH(NH₂)—, —CH₂NH—, —C(O)—,    —C(O)NH(CH₂)₀₋₄—, —C(O)N(CH₃)CH₂CH₂—, —NH—, —NHC(O)—, —NHCH₂—,    —NHCH₂C(O)—, —O—, or —OCH₂CH₂—;-   R_(14c) is adamantanyl, azetidinyl, cyclopropyl, cyclohexyl,    diazepanyl, imidazolyl, indolyl, morpholinyl,    octahydropyrrolo[3,4-c]pyrrolyl, phenyl, piperazinonyl, piperazinyl,    piperidinyl, pyridinyl, pyrrolidinonyl, pyrrolidinyl, or tetrazolyl,    each substituted with zero to 1 substituent selected from —OH, —CH₃,    —CH(CH₃)₂, —CH₂CH(CH₃)₂, —C(CH₃)₂OH, —NH₂, —N(CH₃)₂, —NH(C(CH₃)₂,    —NHC(O)CH₃, —C(O)CH₃, —C(O)NH₂, —C(O)N(CH₂CH₃)₂,    —C(O)(tetrahydrofuranyl), —C(O)OCH₂CH₃, —CH₂C(O)NH(CH(CH₃)₂,    morpholinyl, methylpiperidinyl, pyrazinyl, pyridinyl, and    pyrrolidinyl;-   n is zero or 1; and-   p is zero, 1, 2, or 3; and G is defined in the first aspect or the    second aspect.

One embodiment provides a compound of Formula (I), N-oxide, or a saltthereof,

wherein:

-   A is:-   (i) —O-L₁-R₆;-   (ii) —NR₇R₈;-   (iii) -L₂-C(O)NR₉R₁₀;-   (iv) —CHR_(x)R₁₁, —CH₂CH₂R₁₁, —CH₂NH₂, —CH₂NHC(O)R₁₁,    —CH₂NHC(O)CH₂CH₂(piperidinyl), —CH₂NHC(O)OCH₂(piperidinyl), or    —CH₂NHC(O)CH₂CH₂N(CH₃)₂;-   (v) —CHR₁₂R₁₃, wherein R₁₂ and R₁₃ together with the carbon atom to    which they are attached form a cyclic group selected from    azabicyclo[4.1.1]octanyl, azepanyl, azetidinyl, C₃₋₆ cycloalkyl,    diazaspiro[4.5]decanonyl, morpholinyl,    octahydrocyclopenta[c]pyrrolyl, piperidinyl, pyrrolidinyl, and    quinuclidinyl, each substituted with zero to 3 R_(12a);-   (vi) —CH═CH(piperidinyl); or-   (vii) an aromatic group selected from    [1,2,4]triazolo[1,5-a]pyridinyl, imidazo[1,2-a]pyridinyl,    imidazolyl, indazolyl, isoquinolinyl, oxadiazolyl, oxazolyl, phenyl,    pyrazinyl, pyrazolo[3,4-b]pyridinyl, pyrazolyl, pyridazinyl,    pyridinyl, pyrimidinyl, pyrrolyl, quinolinonyl, quinolinyl,    quinoxalinyl, tetrahydro-[1,2,4]triazolo[1,5-a]pyrazinyl,    tetrahydroimidazo[1,2-a]pyrazinyl, tetrahydroisoquinolinyl,    tetrahydrothiazolo[5,4-c]pyridinyl,    tetrahydrothieno[2,3-c]pyridinyl, thiadiazolyl, thiazolyl,    thiooxadiazolyl, and triazolyl, each substituted with zero to 2    R_(14a) and zero to 3 R_(14b);-   L₁ is bond, —CH₂—, —CH₂CH₂—, —CH₂C(O)—, —CH₂C(O)NH—,    —CH₂C(O)N(CH₃)—, —CH₂C(O)NHCH₂—, or —CH₂C(O)NHCH₂CH₂—;-   L₂ is a bond, —CH(CH₃)—, —C(CH₃)₂—, or —CH₂CH₂—;-   R₆ is:    -   (i) —CH₂C(O)NHCH₂C(CH₃)₂OH, —CH₂C(O)NHCH₂CH₂C(CH₃)₂OH,        —CH₂C(O)NHCH₂CH₂NH₂, or —CH₂C(O)NHCH₂CHFC(CH₃)₂OH; or    -   (ii) azabicyclo[3.2.1]octanyl, azaspiro[5.5]undecanyl,        azetidinyl, cyclohexyl, diazabicyclo[2.2.1]heptanyl,        diazaspiro[3.5]nonanyl, morpholinyl,        octahydrocyclopenta[c]pyrrolyl, piperazinyl, piperidinyl,        pyrrolidinyl, or quinuclidinyl, each substituted with zero to 2        R_(6a);-   each R_(6a) is independently F, —OH, —CH₃, —CH₂CH₂CH₃, —C(CH₃)₂,    —CH₂CH(CH₃)₂, —CH₂CH₂CH₂CF₃, —CH₂CH₂OH, —CH₂CH₂CH₂OH, —CH₂CH(CH₃)OH,    —CH₂C(CH₃)₂OH, —CH₂CH₂OCH₃, —NH₂, —N(CH₃)₂, —CH₂NH₂, —CH₂CH₂NH₂,    —CH₂CH₂S(O)₂CH₃, —CH₂C(O)N(CH₃)₂, —C(O)CH₂N(CH₃)₂, oxetanyl,    tetrahydropyranyl, piperidinyl, isobutylpiperidinyl, or    —O(piperidinyl);-   R₇ is:    -   (i) —CH₂(isopropyl azaspiro[3.5]nonanyl),        —CH₂(methylpyrrolidinyl), —C(O)(CH₂)₁₋₃NH₂,        —C(O)CH(NH₂)CH₂CH₂CH₃, —C(O)CH(NH₂)CH₂CH(CH₃)₂,        —C(O)CH(NH₂)CH(CH₃)CH₂CH₃, —C(O)CH(NH₂)CH₂CH₂C(O)OH,        —C(O)CH(NH₂)(CH₂)₃₋₄NH₂, —C(O)CH(NH₂)(CH₂)₁₋₂C(O)NH₂,        —C(O)CH(NH₂)(cyclohexyl), —C(O)CH(NH₂)(phenyl),        —C(O)(aminocyclohexyl), —C(O)(morpholinyl), —C(O)(pyrrolidinyl),        pentamethylpiperidinyl, methylpiperidinyl-piperidinyl,        methylpyrrolidinyl-pyrrolidinyl, or phenyl substituted with        —OCH₂CH₂(pyrrolidinyl) or —OCH₂CH₂NHCH₂CH₃; or    -   (ii) cyclohexyl substituted with —NR_(x)(CH₂)₂₋₃N(CH₃)₂,        —NHCH₂CH₂NHCH₃, —NH(methylpiperidinyl),        —NH(CH₂)₂₋₃(morpholinyl), dimethylamino piperidinyl, or        piperazinyl substituted with —CH₃, —CH₂CH₃, —C(CH₃)₃,        —CH₂CH(CH₃)₂, —C(O)CH₃, —CH₂CH₂OCH₃, —CH₂(methylphenyl),        —(CH₂)₂₋₃(pyrrolidinyl), cyclopentyl, pyridinyl, or        methylpiperidinyl;-   R_(7b) is:    -   (i) —CH₃, —CH(CH₃)₂, —C(CH₃)₂OH, —CH₂CH₂CH₂C≡CH, —CH₂CH₂OCH₃,        —CH₂CH₂S(O)₂CH₃, —(CH₂)₁₋₂NR_(x)R_(x), —CH₂C(O)NR_(x)R_(x),        —NR_(x)R_(y), —NR_(x)(C₁₋₄ hydroxyalkyl), —NR_(y)(C₁₋₂        cyanoalkyl), —NR_(x)(C₁₋₂ fluoroalkyl), —NR_(x)(C₂₋₄        hydroxyfluoroalkyl), —NR_(x)(CH₂)₁₋₂C(O)NR_(x)R_(x),        —NR_(x)(CH₂)₁₋₃NR_(x)R_(x), —NR_(x)CH₂CH₂N(CH₃)₂,        —NR_(x)C(O)(CH₂)₁₋₂NR_(x)R_(x), —OCH₂CH₂N(CH₃)₂,        —C(O)CH₂NR_(x)R_(x), —(CH₂)₁₋₂R_(7d), —NHR_(7d),        —NH(CH₂)₁₋₂R_(7d), or —OR_(7d); or    -   (ii) azepanyl, azetidinyl, diazepanyl, dioxothiomorpholinyl,        morpholinyl, oxaazaspiro[3.3]heptanyl, oxetanyl, piperazinonyl,        piperazinyl, piperidinyl, pyridinyl, pyrrolidinonyl,        pyrrolidinyl, or tetrahydroisoquinolinyl, each substituted with        zero to 1 R_(8a) and zero to 3 R_(8b);-   each R_(7c) is independently —CH₃ or —CH₂CN;-   R_(7d) is azaspiro[3.5]nonanyl, bicyclo[1.1.1]pentanyl, C₃₋₆    cycloalkyl, morpholinyl, oxetanyl, phenyl, piperidinyl, pyrazolyl,    pyrrolidinyl, tetrahydrofuranyl, or tetrahydropyranyl, each    substituted with zero to 1 substituent selected from C₁₋₃ alkyl,    —NH₂, —C(O)CH₃, methylpiperidinyl, methylpyrrolidinyl,    tetramethylpiperidinyl, —OCH₂CH₂(pyrrolidinyl), and    —OCH₂CH₂NHCH₂CH₃; and zero to 4 substituents selected from —CH₃;-   R₈ is H, —CH₃ or —CH₂CH₃;-   or R₇ and R₈ together with the nitrogen atom to which they are    attached form a heterocyclic ring selected from azetidinyl,    diazepanonyl, diazepanyl, diazaspiro[3.5]nonanyl,    diazaspiro[5.5]undecanyl, imidazolidinonyl,    octahydro-TH-pyrrolo[3,4-b]pyridinyl, piperazinyl, piperidinyl,    pyrrolidinonyl, and pyrrolidinyl, wherein said heterocyclic ring is    substituted with zero to 1 R_(7b) and zero to 2 R_(7c);-   R_(8a) is —OH, —CH₃, —CH₂CH₃, —CH(CH₃)₂, —C(CH₃)₃, —CH₂CH(CH₃)₂,    —CH₂CH₂OCH₃, —CH₂CH₂CF₃, —C(O)CH₃, —CH₂(cyclopropyl), —CH₂(methyl    phenyl), —(CH₂)₂₋₃(pyrrolidinyl), —CH₂(methylpyrazolyl),    —CH₂(thiophenyl), —NR_(x)R_(x), cyclopentyl, methylpiperidinyl, or    pyridinyl;-   each R_(8b) is —CH₃;-   R₉ is —CH₃, —CH₂CH₂OH, —CH₂C(CH₃)₂OH, —CH₂C(CH₃)₂CH₂OH,    —CH₂CHFC(CH₃)₂OH, —CH₂CH₂C(CH₃)₂OH, —CH(CH₂OH)₂, —CH₂CH₂OCH₃,    —CH₂CH₂NH₂, —CH₂CH₂N(CH₃)₂, —CH₂CH₂CH₂N(CH₃)₂, —CH₂CH₂C(O)NH₂,    —CH₂S(O)₂OH, —CH₂CH₂C(CH₃)₂NHS(O)₂CH₃, or —(CH₂)₀₋₃R_(9a);-   R_(9a) is cyclohexyl, cycloheptyl, furanyl, phenyl, piperazinyl,    piperidinyl, pyrazolyl, pyridinyl, pyrrolidinyl, quinuclidinyl,    thiazolyl, or octahydrocyclopenta[c]pyrrolyl, each substituted with    zero to 2 substituents independently selected from —OH, C₁₋₃ alkyl,    —NH₂, —N(CH₃)₂, oxetanyl, phenyl, piperazinyl, piperidinyl, and    pyrrolidinyl;-   R₁₀ is H, —CH₃, —CH₂CH₃, —CH₂CH₂OCH₃, or cyclopropyl;-   or R₉ and R₁₀ together with the nitrogen atom to which they are    attached form a heterocyclic ring selected from    azabicyclo[3.1.1]heptanyl, azaspiro[5.5]undecanyl,    diazabicyclo[2.2.1]heptanyl, diazabicyclo[3.1.1]heptanyl,    diazabicyclo[3.2.0]heptanyl, diazaspiro[3.5]nonanyl,    diazaspiro[4.4]nonanyl, diazaspiro[4.5]decanyl, diazepanyl,    indolinyl, morpholinyl, octahydropyrrolo[3,4-c]pyrrolyl,    piperazinonyl, piperazinyl, piperidinyl, and pyrrolidinyl, each    substituted with zero to 2 R_(10a);-   each R_(10a) is independently —CH₃, —CH₂CH₃, —CH(CH₃)₂, —CH₂OH,    —CH₂CH₂OH, —CH₂OCH₃, —CH₂CH₂OCH₃, —CH₂NH₂, —CH₂CH₂NH₂,    —CH₂CH₂NH(CH₃), —CH₂C(O)NH(CH₃), —CH₂C(O)N(CH₃)₂,    —CH₂(methyltriazolyl), —CH₂CH₂(phenyl), —CH₂CH₂(morpholinyl),    —C(O)CH₃, —C(O)NH₂, —C(O)N(CH₂CH₃)₂, —C(O)CH₂NH(CH₃),    —C(O)CH₂N(CH₃)₂, —NH₂, —N(CH₃)₂, —NHC(O)CH₃, —C(O)(furanyl),    —O(piperidinyl), —C(O)CH₂(diethylcarbamoylpiperidinyl),    methylpiperazinyl, piperidinyl, methylpiperidinyl,    diethylcarbamoylpiperidinyl, isopropylpiperidinyl, pyridinyl,    trifluoromethylpyridinyl, pyrimidinyl, or    dihydrobenzol[d]imidazolonyl;-   R₁₁ is azetidinyl, azaspiro[3.5]nonanyl, dioxidothiomorpholinyl,    hexahydropyrrolo[3,4-c]pyrrolyl, morpholinyl, piperazinyl,    piperidinyl, or pyrrolidinyl, each substituted with zero to 2    substituents independently selected from F, —CH₃, —CH(CH₃)₂, —CH₂CN,    —CH₂(phenyl), —C(O)CH₂N(CH₃)₂, —CH₂C(CH₃)₂OH, —CH₂C(O)N(CH₃)₂,    —CH₂CH₂S(O)₂CH₃, —CH₂CH₂S(O)CH₃, oxetanyl, and tetrahydropyranyl;-   each R_(12a) is independently —OH, —CH₃, —CH₂CH₂CH₃, —CH(CH₃)₂,    —CH₂CH(CH₃)₂, —CF₃, —CH₂CF₃, —CH₂CH₂CH₂CF₃, —CH₂CN, —CH₂C(CH₃)₂OH,    —CH₂CH₂OCH₃, —CH₂C(O)NH(CH₃), —CH₂C(O)N(CH₃)₂, —CH₂C(O)NH₂,    —CH₂CH₂S(O)₂CH₃, —CH₂CH₂NHS(O)₂CH₃, —CH₂NR_(x)R_(x), —CH₂CH₂NH(CH₃),    —OCH₃, —NR_(x)R_(y), —NR_(x)(C₂₋₄ fluoroalkyl),    —NR_(x)(CH₂CR_(x)R_(x)OCH₃), —NH(CH₂CN), —N(CH₃)CH₂N(CH₃)₂,    —NH(CH₂C(CH₃)₂OH), —NR_(x)(CH₂C(O)NH₂), —N(CH₃)(OCH₃),    —NR_(x)CH₂CH₂S(O)₂CH₃, —NHC(O)CH₃, —NHC(O)CH₂CF₃,    —NHC(O)CHR_(x)NH(CH₃), —NR_(x)C(O)CH₂N(CH₃)₂,    —NHC(O)CH₂N(CH₃)(CH₂CH₃), —NHC(O)CH₂N(CH₂CH₃)₂,    —NHC(O)CH₂NH(CH₂C(CH₃)₂OH), —NHCH₂C(O)NR_(x)(CH₃), —NHS(O)₂CH₃,    —C(O)C(CH₃)₃, —C(O)CH(CH₂CH₃)₂, —C(O)CH₂OCH₃, —C(O)CH₂CH₂OCH₃,    —C(O)CH₂NH(CH₃), —C(O)CH₂N(CH₃)₂, —C(O)CH(CH₃)NH(CH₃),    —C(O)CH₂N(CH₃)(CH₂CH₃), —C(O)CH₂N(CH₂CH₃)₂, R_(12b), —CH₂R_(12b),    —C(O)R_(12b), —C(O)CH₂R_(12b), —C(O)CH₂NHR_(12b),    —C(O)NR_(x)R_(12b), —NR_(x)C(O)CH₂R_(12b), —NR_(x)R_(12b),    —NR_(x)CH₂R_(12b), —N(CH₂CN)R_(12b), —NHC(O)CH₂NR_(x)R_(12b),    —NHC(O)CH₂NR_(x)CH₂R_(12b), —NHCH₂C(O)NHR_(12b), or —OR_(12b); or    two R_(12a) and the carbon atom to which they are attached form C═O;-   R_(12b) is azetidinyl, bicyclo[1.1.1]pentanyl, cyclopropyl,    diazabicyclo[2.2.1]heptanyl, dioxolanyl,    dioxidotetrahydrothiopyranyl, dioxidothiomorpholinyl, imidazolyl,    morpholinyl, octahydrocyclopenta[c]pyrrolyl,    octahydropyrrolo[3,4-c]pyrrolyl, oxaazaspiro[3.3]heptanyl, oxetanyl,    phenyl, piperazinyl, piperazinonyl, piperidinyl, pyridinyl,    pyrrolidinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydropyranyl,    or triazolyl, each substituted with zero to 4 substituents    independently selected from F, —OH, —CH₃, —CH(CH₃)₂, —CH₂OH, —OCH₃,    —CH₂CH₂OCH₃, —NR_(x)R_(x), —C(O)NH₂, and —CH₂S(O)₂CH₃;-   each R_(14a) is independently:    -   (i) H, F, Cl, —OH, —CH₃, —CH(CH₃)₂, —CH(CH₃)(CH₂CH₃),        —CH₂CH₂CH₂C(CH₃)₂, —CF₃, —CH₂CF₃, —CH₂OH, —OCH₃, —CH₂CH₂OCH₃,        —CHR_(x)NR_(x)(CH₃), —CH₂N(CH₃)(CH(CH₃)₂), —CH₂NH(CH₂C(CH₃)₃),        —CH₂NH(CH₂CN), —CH₂N(CH₃)(CH₂CH₂OCH₃), —CH₂N(CH₂CH₂OCH₃)₂,        —CH₂NR_(x)(CH₂C≡CH), —CH₂NHCH₂CH₂N(CH₃)₂, —CH₂CH₂NR_(x)(CH₃),        —CH₂CR_(x)(CH₃)NH₂, —CH₂CH₂CH₂N(CH₃)₂, —CH₂CH₂CH₂CH₂NH₂,        —CH(NH₂)(CH₂)₃₋₄NH₂, —CH₂NHCH₂CH₂O(C₁₋₃ alkyl),        —CH₂NHCH₂CH₂OCH₂CH₂OH, —CH₂NHCH₂CH₂S(O)₂OH, —CH₂C(O)NR_(x)(CH₃),        —NR_(x)R_(x), —NH(CH(CH₃)₂), —NHCH₂CH₂NH(CH₃),        —NHCH₂CH₂CH₂N(CH₃)₂, —NHC(O)CH₃, —NHC(O)CF₃, —NHC(O)OC(CH₃)₃,        —NHC(O)CH₂N(CH₃)₂, —NHC(O)CH₂CH₂N(CH₃)₂, —NHCH₂C(O)CH₂NH(CH₃),        —C(O)CH₃, —C(O)CH₂CH(CH₃)OH, —C(O)CH₂NR_(x)(CH₃),        —C(O)NR_(x)R_(x), —C(O)NH(CH₂CN), —C(O)NHCH₂CH₂CH₂NR_(x)R_(x),        —C(O)NHCH₂CH(CH₃)CH₂NH₂, —C(O)NHCH₂C(O)NH₂,        —C(O)N(CH₃)CH₂CH₂CH₂N(CH₃)₂, —C(O)N(CH₂CH₃)CH₂CH₂N(CH₃)₂,        —OCH₂CH₂CH₂N(CH₃)₂, —C(O)NHCH₂CH₂NHC(O)CH₃, —S(O)₂NH₂, or        —C(O)CH₂S(O)₂CH₃;    -   (ii) 8-azabicyclo[3.2.1]octanyl, azaspiro[3.5]nonanyl,        azetidinyl, benzo[c][1,2,5]oxadiazolyl, cyclopentyl, cyclohexyl,        diazepanyl, morpholinyl, phenyl, piperazinyl, piperidinyl,        pyrazolyl, pyridinyl, pyrrolidinonyl, quinolinyl, quinuclidinyl,        tetrahydroisoquinolinyl, tetrahydropyridinyl, or thiazolidinyl,        each substituted with zero to 2 substituents independently        selected from —CH₃, —CH(CH₃)₂, —CH₂CH(CH₃)₂, —CF₃, —CH₂CH₂CF₃,        —CH₂CH₂OH, —CH₂CH₂CH(CH₃)OH, —NH₂, —CH₂N(CH₃)₂, —CH₂CH₂NH(CH₃),        —C(O)CH₃, —C(O)CH₂NH(CH₃), —C(O)CH₂N(CH₃)₂, —C(O)O(C(CH₃)₃),        —CH₂C(O)NR_(x)(CH₃), cyclobutyl, cyclopentyl, —CH₂(phenyl),        —CH₂(pyrrolyl), —CH₂(morpholinyl), —CH₂(methylpiperazinyl),        —CH₂(thiophenyl), methylpiperidinyl, isobutylpiperidinyl, and        pyridinyl; or    -   (iii) -L₃-R_(14c);-   each R_(14b) is —CH₃;-   L₃ is —(CH₂)₁₋₃—, —CH(CH₃)—, —CH(NH₂)—, —CH₂NH—, —C(O)—,    —C(O)NH(CH₂)₀₋₄—, —C(O)N(CH₃)CH₂CH₂—, —NH—, —NHC(O)—, —NHCH₂—,    —NHCH₂C(O)—, —O—, or —OCH₂CH₂—;-   R_(14c) is adamantanyl, azetidinyl, cyclopropyl, cyclohexyl,    diazepanyl, imidazolyl, indolyl, morpholinyl,    octahydropyrrolo[3,4-c]pyrrolyl, phenyl, piperazinonyl, piperazinyl,    piperidinyl, pyridinyl, pyrrolidinonyl, pyrrolidinyl, or tetrazolyl,    each substituted with zero to 1 substituent selected from —OH, —CH₃,    —CH(CH₃)₂, —CH₂CH(CH₃)₂, —C(CH₃)₂OH, —NH₂, —N(CH₃)₂, —NH(C(CH₃)₂,    —NHC(O)CH₃, —C(O)CH₃, —C(O)NH₂, —C(O)N(CH₂CH₃)₂,    —C(O)(tetrahydrofuranyl), —C(O)OCH₂CH₃, —CH₂C(O)NH(CH(CH₃)₂,    morpholinyl, methylpiperidinyl, pyrazinyl, pyridinyl, and    pyrrolidinyl;-   n is zero or 1; and-   p is zero, 1, 2, or 3; and G is defined in the first aspect or the    second aspect.

One embodiment provides a compound of Formula (I), N-oxide, or a saltthereof wherein:

-   G is:

-   A is:-   (i) —NR₇R₈ wherein R₇ and R₈ together with the nitrogen atom to    which they are attached form a heterocyclic ring selected from    piperazinyl, piperidinyl, or diazaspiro[3.3]heptanyl, wherein said    heterocyclic ring is substituted with zero to 1 R_(7b) and zero to 1    R_(7c); or-   (ii) —CHR₁₂R₁₃, wherein R₁₂ and R₁₃ together with the carbon atom to    which they are attached form a cyclic group selected from    cyclopentyl, cyclohexyl, morpholinyl, or piperidinyl, each    substituted with zero to 1 R_(12a);-   R₁ is —CH₃ or —CH(CH₃)₂;-   each R₂ is independently —CH₃ or —OCH₃;-   R₅ is F, Cl, or —CH₃;-   R_(7b) is:    -   (i) —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, —CH(CH₃)₂, —CH₂CH(CH₃)₂, —CH₂CF₃,        —CH₂CN, —CH₂C(CH₃)₂OH, —CH₂CH₂OCH₃, —CH₂CH₂S(O)₂CH₃,        —(CH₂)₁₋₂NR_(x)R_(x), —CH₂C(O)NR_(x)R_(x), —NR_(x)R_(y),        —NR_(x)(C₁₋₄ hydroxyalkyl), —NH(CH₂CR_(x)R_(x)OCH₃),        —NR_(y)(C₁₋₂ cyanoalkyl), —NR_(x)(C₁₋₂ fluoroalkyl),        —NR_(x)(C₂₋₅ hydroxyfluoroalkyl),        —NR_(x)(CH₂)₁₋₂C(O)NR_(x)R_(x), —NR_(x)(CH₂)₁₋₃NR_(x)R_(x),        —NR_(x)CH₂CH₂N(CH₃)₂, —NR_(x)C(O)(CH₂)₁₋₂NR_(x)R_(x), —C(O)CH₃,        —C(O)CH₂NR_(x)R_(x), —S(O)₂CH₃, —(CH₂)₁₋₂R_(7d), —CH₂C(O)R_(7d),        —C(O)CH₂R_(7d), —NHR_(7d), —NH(CH₂)₁₋₂R_(7d), or —OR_(7d); or    -   (ii) azetidinyl, bicyclo[1.1.1]pentanyl, cyclobutyl,        dioxothiomorpholinyl, morpholinyl, oxaazaspiro[3.3]heptanyl,        oxetanyl, piperazinonyl, piperazinyl, piperidinyl,        tetrahydrofuranyl, or tetrahydropyranyl, each substituted with        zero to 1 R_(8a);-   R_(7c) is —CH₃;-   R_(8a) is —CH₃, —CH(CH₃)₂, or —S(O)₂CH₃;-   R_(12a) is —CH(CH₃)₂, —CH₂CF₃, —CH₂C(CH₃)₂OH, —CH₂CH₂OCH₃,    —CH₂C(O)NH(CH₃), —CH₂C(O)N(CH₃)₂, —CH₂C(O)NH₂, —CH₂CH₂S(O)₂CH₃,    —CH₂CH₂NH(CH₃), —NR_(x)R_(y), —NR_(x)(C₂₋₄ fluoroalkyl),    —NH(CH₂C(CH₃)₂OH), —NH(CH₂CHFC(CH₃)₂OH), —NH(CH₂CH₂OCH₃),    —NH(CH₂C(CH₃)₂₀CH₃), —NR_(x)(CH₂C(O)NR_(x)R_(x)), —C(O)CH₂NH(CH₃),    —C(O)CH₂N(CH₃)₂, R_(12b), —CH₂R_(12b), —NR_(x)R_(12b),    —N(CH₂CN)R_(12b), or —NR_(x)CH₂R_(12b);-   R_(12b) is azetidinyl, bicyclo[1.1.1]pentanyl,    oxaazaspiro[3.3]heptanyl, oxetanyl, piperidinyl, tetrahydrofuranyl,    or tetrahydropyranyl, each substituted with zero to 4 substituents    independently selected from —CH₃, —CH(CH₃)₂, —CH₂OH, or —OCH₃; and n    is zero or 1.

One embodiment provides a compound of Formula (I), N-oxide, or a saltthereof wherein:

-   G is:

-   A is:-   (i) —NR₇R₈ wherein R₇ and R₈ together with the nitrogen atom to    which they are attached form a heterocyclic ring selected from    piperazinyl or piperidinyl, wherein said heterocyclic ring is    substituted with zero to 1 R_(7b); or-   (ii) —CHR₁₂R₁₃, wherein R₁₂ and R₁₃ together with the carbon atom to    which they are attached form a cyclic group selected from    cyclopentyl, cyclohexyl, morpholinyl, or piperidinyl, each    substituted with zero to 1 R_(12a);-   R₁ is —CH₃ or —CH(CH₃)₂;-   each R₂ is independently —CH₃ or —OCH₃;-   R₅ is F, Cl, or —CH₃;-   R_(7b) is:    -   (i) —CH₂CH₂OCH₃, —CH₂CH₂S(O)₂CH₃, —(CH₂)₁₋₂NR_(x)R_(x),        —CH₂C(O)NR_(x)R_(x), —NR_(x)R_(y), —NR_(x)(C₁₋₄ hydroxyalkyl),        —NR_(y)(C₁₋₂ cyanoalkyl), —NR_(x)(C₁₋₂ fluoroalkyl),        —NR_(x)(C₂₋₄ hydroxyfluoroalkyl),        —NR_(x)(CH₂)₁₋₂C(O)NR_(x)R_(x), —NR_(x)(CH₂)₁₋₃NR_(x)R_(x),        —NR_(x)CH₂CH₂N(CH₃)₂, —NR_(x)C(O)(CH₂)₁₋₂NR_(x)R_(x),        —C(O)CH₂NR_(x)R_(x), —(CH₂)₁₋₂R_(7d), —NHR_(7d),        —NH(CH₂)₁₋₂R_(7d), or —OR_(7d); or    -   (ii) azetidinyl, dioxothiomorpholinyl, morpholinyl,        oxaazaspiro[3.3]heptanyl, oxetanyl, piperazinonyl, or        piperazinyl, each substituted with zero to 1 R_(8a);-   R_(8a) is —CH₃ or —S(O)₂CH₃;-   R_(12a) is —CH(CH₃)₂, —CH₂CF₃, —CH₂C(CH₃)₂OH, —CH₂CH₂OCH₃,    —CH₂C(O)NH(CH₃), —CH₂C(O)N(CH₃)₂, —CH₂C(O)NH₂, —CH₂CH₂S(O)₂CH₃,    —CH₂CH₂NH(CH₃), —NR_(x)R_(y), —NR_(x)(C₂₋₄ fluoroalkyl),    —NH(CH₂C(CH₃)₂OH), —NH(CH₂C(CH₃)₂₀CH₃), —NR_(x)(CH₂C(O)NH₂),    —NHCH₂C(O)NR_(x)(CH₃), —C(O)CH₂NH(CH₃), —C(O)CH₂N(CH₃)₂, R_(12b),    —CH₂R_(12b), —NR_(x)R_(12b), or —NR_(x)CH₂R_(12b),;-   R_(12b) is azetidinyl, bicyclo[1.1.1]pentanyl,    oxaazaspiro[3.3]heptanyl, oxetanyl, piperidinyl, tetrahydrofuranyl,    or tetrahydropyranyl, each substituted with zero to 4 substituents    independently selected from —CH₃, —CH(CH₃)₂, —CH₂OH, or —OCH₃; and-   n is zero or 1.

One embodiment provides a compound of Formula (I), N-oxide, or a saltthereof, wherein R₁ is H, Cl, —CN, C₁₋₄ alkyl, C₁₋₂ fluoroalkyl, C₁₋₂hydroxyalkyl, or —C(O)O(C₁₋₂ alkyl); and G, A, R₅, n, and p are definedin the first aspect or the second aspect. Included in this embodimentare compounds in which R₁ is —CH₃, —CH₂CH₃, —CH(CH₃)₂, —CH₂CHF₂, or—CH₂CF₃. Also included in this embodiment are compounds in which R₁ is—CH(CH₃)₂.

One embodiment provides a compound of Formula (I), N-oxide, or a saltthereof, wherein each R₂ is independently F, Cl, —CN, —OH, C₁₋₃ alkyl,C₁₋₂ fluoroalkyl, C₁₋₂ cyanoalkyl, C₁₋₃ hydroxyalkyl, C₁₋₂ aminoalkyl,—(CH₂)₀₋₂O(C₁₋₃ alkyl), C₃₋₆ cycloalkyl, —NR_(x)R_(x),—(CH₂)₀₋₂C(O)NR_(x)R_(x), —(CH₂)₀₋₂S(O)₂(C₁₋₃ alkyl), —CH₂(C₃₋₆cycloalkyl), —CH₂(phenyl), or phenyl; and G, A, R₁, R₅, R_(x), n, and pare defined in the first aspect or the second aspect. Included in thisembodiment are compounds in which each R₂ is independently Cl, —CH₃,—CH₂CH₃, —CH₂OH, —CH₂CH₂OH, —OCH₃, —CH₂OCH₃, or —CH₂CH₂S(O)₂CH₃.

One embodiment provides a compound of Formula (I), N-oxide, or a saltthereof wherein A is —O-L₁-R₆; and G, R₁, R₅, R₆, L₁, n, and p aredefined in the first aspect or the second aspect. Included in thisembodiment are compounds in which L₁ is bond, —(CR_(x)R_(x))₁₋₂—,—CH₂C(O)—, —CH₂C(O)NR_(x)(CR_(x)R_(x))₀₋₂—, —CH₂NR_(x)C(O)—, or—CH₂NR_(x)C(O)CH₂—; and each R_(6a) is independently F, —OH, C₁₋₄ alkyl,C₁₋₄ fluoroalkyl, C₁₋₄ hydroxyalkyl, —(CH₂)₁₋₂OCH₃, —NR_(x)R_(x),—(CH₂)₁₋₂NR_(x)R_(x), —(CH₂)₁₋₂S(O)₂(C₁₋₂ alkyl),—(CH₂)₁₋₂C(O)NR_(x)R_(x), —C(O)CH₂NR_(x)R_(x), oxetanyl,tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, isobutylpiperidinyl,piperazinyl, or —O(piperidinyl).

One embodiment provides a compound of Formula (I), N-oxide, or a saltthereof wherein A is —NR₇R₈; and G, R₁, R₅, R₇, R₈, R_(x), n, and p aredefined in the first aspect or the second aspect. Included in thisembodiment are compounds in which R₇ is: (i) R_(7a), —CH₂R_(7a),—C(O)R_(7a), —C(O)CH(NH₂)R_(7a), —C(O)(CH₂)₁₋₃NH₂, —C(O)CH(NH₂)(C₁₋₄alkyl), —C(O)CH(NH₂)(CH₂)₁₋₂C(O)OH, —C(O)CH(NH₂)(CH₂)₂₋₄NH₂, or—C(O)CH(NH₂)(CH₂)₁₋₃C(O)NH₂; or (ii) C₃₋₆ cycloalkyl substituted withone substituent selected from —NR_(x)(CH₂)₂₋₃NR_(x)R_(x),—NH(CH₂)₂₋₃NHCH₃, —NH(methylpiperidinyl), —NH(CH₂)₂₋₃(morpholinyl),dimethylamino piperidinyl, and piperazinyl substituted with asubstituent selected from C₁₋₄ alkyl, —C(O)CH₃, —(CH₂)₁₋₂OCH₃,—CH₂(methylphenyl), —(CH₂)₂₋₃(pyrrolidinyl), C₃₋₆ cycloalkyl, pyridinyl,and methylpiperidinyl; R_(7b) is: (i) C₁₋₄ alkyl, C₁₋₃ hydroxyalkyl,—(CH₂)₂₋₃C≡CH, —(CH₂)₁₋₂O(C₁₋₂ alkyl), —(CH₂)₁₋₂S(O)₂(C₁₋₂ alkyl),—(CH₂)₀₋₃NR_(x)R_(y), —CH₂C(O)NR_(x)R_(x), —NR_(x)(C₁₋₄ hydroxyalkyl),—NR_(y)(C₁₋₂ cyanoalkyl), —NR_(x)(C₁₋₂ fluoroalkyl), —NR_(x)(C₂₋₄hydroxyfluoroalkyl), —NR_(x)(CH₂)₁₋₂C(O)NR_(x)R_(x),—NR_(x)(CH₂)₁₋₃NR_(x)R_(x), —NR_(x)CH₂CH₂NR_(x)R_(x),—NR_(x)C(O)(CH₂)₁₋₂NR_(x)R_(x), —O(CH₂)₁₋₃NR_(x)R_(x),—C(O)CH₂NR_(x)R_(x), —(CH₂)₁₋₂R_(7d), —NHR_(7d), —NH(CH₂)₁₋₂R_(7d), or—OR_(7d); or (ii) azepanyl, azetidinyl, diazepanyl,dioxothiomorpholinyl, morpholinyl, oxaazaspiro[3.3]heptanyl, oxetanyl,piperazinonyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinonyl,pyrrolidinyl, or tetrahydroisoquinolinyl, each substituted with zero to1 R_(8a) and zero to 3 R_(8b); R_(7d) is azaspiro[3.5]nonanyl,bicyclo[1.1.1]pentanyl, C₃₋₆ cycloalkyl, morpholinyl, oxetanyl, phenyl,piperidinyl, pyrazolyl, pyrrolidinyl, tetrahydrofuranyl, ortetrahydropyranyl, each substituted with zero to 1 substituent selectedfrom C₁₋₃ alkyl, —NH₂, —C(O)CH₃, methylpiperidinyl, methylpyrrolidinyl,tetramethylpiperidinyl, —OCH₂CH₂(pyrrolidinyl), and —OCH₂CH₂NHCH₂CH₃;and zero to 4 substituents selected from —CH₃; and R₈ is H or C₁₋₂alkyl; R_(8a) is —OH, C₁₋₄ alkyl, C₁₋₃ fluoroalkyl, —(CH₂)₁₋₂O(C₁₋₂alkyl), —C(O)(C₁₋₂ alkyl), —CH₂(C₃₋₆ cycloalkyl), —(CH₂)₁₋₂(methylphenyl), —(CH₂)₁₋₃(pyrrolidinyl), —(CH₂)₁₋₂(methylpyrazolyl),—(CH₂)₁₋₂(thiophenyl), —NR_(x)R_(x), C₃₋₆ cycloalkyl, methylpiperidinyl,or pyridinyl; and each R_(8b) is independently F or —CH₃.

One embodiment provides a compound of Formula (I), N-oxide, or a saltthereof wherein A is —NR₇R₈; and G, R₁, R₅, R₇, R₈, n, and p are definedin the first aspect or the second aspect. Included in this embodimentare compounds in which R₇ and R₈ together with the nitrogen atom towhich they are attached form a heterocyclic ring selected fromazetidinyl, diazepanonyl, diazepanyl, diazaspiro[3.5]nonanyl,diazaspiro[5.5]undecanyl, imidazolyl, imidazolidinonyl,octahydro-1H-pyrrolo[3,4-b]pyridinyl, piperazinyl, piperidinyl,pyrrolidinonyl, pyrrolidinyl, and pyrrolyl, wherein said heterocyclicring is substituted with zero to 1 R_(7b) and zero to 2 R_(7c); R_(7b)is: (i) C₁₋₄ alkyl, C₁₋₃ hydroxyalkyl, —(CH₂)₂₋₃C≡CH, —(CH₂)₁₋₂O(C₁₋₂alkyl), —(CH₂)₁₋₂S(O)₂(C₁₋₂ alkyl), —(CH₂)₀₋₃NR_(x)R_(y),—CH₂C(O)NR_(x)R_(x), —NR_(x)(C₁₋₄ hydroxyalkyl), —NR_(y)(C₁₋₂cyanoalkyl), —NR_(x)(C₁₋₂ fluoroalkyl), —NR_(x)(C₂₋₄hydroxyfluoroalkyl), —NR_(x)(CH₂)₁₋₂C(O)NR_(x)R_(x),—NR_(x)(CH₂)₁₋₃NR_(x)R_(x), —NR_(x)CH₂CH₂NR_(x)R_(x),—NR_(x)C(O)(CH₂)₁₋₂NR_(x)R_(x), —O(CH₂)₁₋₃NR_(x)R_(x),—C(O)CH₂NR_(x)R_(x), —(CH₂)₁₋₂R_(7d), —NHR_(7d), —NH(CH₂)₁₋₂R_(7d), or—OR_(7d); or (ii) azepanyl, azetidinyl, diazepanyl,dioxothiomorpholinyl, morpholinyl, oxaazaspiro[3.3]heptanyl, oxetanyl,piperazinonyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinonyl,pyrrolidinyl, or tetrahydroisoquinolinyl, each substituted with zero to1 R_(8a) and zero to 3 R_(8b); each R_(7c) is independently F, —CH₃ or—CH₂CN; R_(8a) is —OH, C₁₋₄ alkyl, C₁₋₃ fluoroalkyl, —(CH₂)₁₋₂O(C₁₋₂alkyl), —C(O)(C₁₋₂ alkyl), —CH₂(C₃₋₆ cycloalkyl), —(CH₂)₁₋₂(methylphenyl), —(CH₂)₁₋₃(pyrrolidinyl), —(CH₂)₁₋₂(methylpyrazolyl),—(CH₂)₁₋₂(thiophenyl), —NR_(x)R_(x), C₃₋₆ cycloalkyl, methylpiperidinyl,or pyridinyl; and each R_(8b) is independently F or —CH₃.

One embodiment provides a compound of Formula (I), N-oxide, or a saltthereof wherein A is —(CR_(x)R_(x))₁₋₃R₁₁,—(CR_(x)R_(x))₁₋₃NR_(x)C(O)R₁₁, or—(CR_(x)R_(x))₁₋₂NR_(x)C(O)(CH₂)₁₋₂NR_(x)R_(x); and G, R₁, R₅, R₁,R_(x), n, and p are defined in the first aspect or the second aspect.Included in this embodiment are compounds in which Rn is azetidinyl,azaspiro[3.5]nonanyl, dioxidothiomorpholinyl,hexahydropyrrolo[3,4-c]pyrrolyl, morpholinyl, piperazinyl, piperidinyl,pyridinyl, or pyrrolidinyl, each substituted with zero to 3 substituentsindependently selected from F, Cl, —CN, C₁₋₃ alkyl, C₁₋₂ aminoalkyl,—CH₂(phenyl), —C(O)CH₂NR_(x)R_(x), —CH₂CR_(x)R_(x)OH,—CH₂C(O)NR_(x)R_(x), —CH₂CH₂S(O)₂(C₁₋₃ alkyl), —CH₂CH₂S(O)(C₁₋₃ alkyl),oxetanyl, tetrahydrofuranyl, and tetrahydropyranyl.

One embodiment provides a compound of Formula (I), N-oxide, or a saltthereof wherein A is —CR_(x)R₁₂R₁₃, wherein R₁₂ and R₁₃ together withthe carbon atom to which they are attached form a cyclic group selectedfrom azabicyclo[4.1.1]octanyl, azepanyl, azetidinyl, C₃₋₇ cycloalkyl,diazepanyl, diazaspiro[4.5]decanonyl, morpholinyl,octahydrocyclopenta[c]pyrrolyl, piperazinyl, piperidinyl, pyrrolidinyl,and quinuclidinyl, each substituted with zero to 4 R_(12a); and G, R₁,R₅, R₁₂, R₁₃, R_(x), R_(y), n, and p are defined in the first aspect orthe second aspect. Included in this embodiment are compounds in whicheach R_(12a) is independently —OH, C₁₋₄ alkyl, C₁₋₃ fluoroalkyl, C₁₋₂cyanoalkyl, C₁₋₄ hydroxyalkyl, —(CH₂)₁₋₂O(C₁₋₂ alkyl),—CH₂C(O)NR_(x)R_(x), —(CH₂)₁₋₂S(O)₂(C₁₋₂ alkyl), —(CH₂)₁₋₂NHS(O)₂(C₁₋₂alkyl), —(CH₂)₁₋₂NR_(x)R_(x), C₁₋₂ alkoxy, —NR_(y)R_(y), —NR_(x)(C₁₋₃fluoroalkyl), —NR_(x)(CH₂CH₂O(C₁₋₂ alkyl)), —NR_(x)(C₁₋₂ cyanoalkyl),—NR_(x)CH₂NR_(x)R_(x), —NR_(x)(C₁₋₄ hydroxyalkyl), —NR_(x)(CH₂C(O)NH₂),—NR_(x)(OCH₃), —NR_(x)CH₂CH₂S(O)₂(C₁₋₂ alkyl), —NR_(x)C(O)CH₃,—NR_(x)C(O)(C₁₋₂ fluoroalkyl), —NR_(x)C(O)CR_(x)R_(x)NR_(x)R_(x),—NR_(x)C(O)CH₂NR_(y)R_(y), —NR_(x)C(O)CH₂NR_(x)(C₁₋₄ hydroxyalkyl),—NR_(x)CH₂C(O)NR_(x)R_(x), —NR_(x)S(O)₂CH₃, —C(O)(C₁₋₅ alkyl),—C(O)CH₂O(C₁₋₂ alkyl), —C(O)CH₂CH₂O(C₁₋₂ alkyl), —C(O)CH₂NR_(x)R_(x),—C(O)CHR_(x)NR_(y)R_(y), R_(12b), —CR_(x)R_(x)R_(12b), —C(O)R_(12b),—C(O)CH₂NR_(x)R_(12b), —C(O)NR_(x)R_(12b),—NR_(x)C(O)CR_(x)R_(x)R_(12b), —NR_(x)R_(12b),—NR_(x)CR_(x)R_(x)R_(12b), —NR_(x)C(O)CH₂NR_(x)R_(12b),—NR_(x)C(O)CH₂NR_(x)CH₂R_(12b), —NR_(x)CH₂C(O)NR_(x)R_(12b), or—OR_(12b); and R_(12b) is azetidinyl, bicyclo[1.1.1]pentanyl, C₃₋₆cycloalkyl, diazabicyclo[2.2.1]heptanyl, dioxolanyl,dioxidotetrahydrothiopyranyl, dioxidothiomorpholinyl, imidazolyl,morpholinyl, octahydrocyclopenta[c]pyrrolyl,octahydropyrrolo[3,4-c]pyrrolyl, oxaazaspiro[3.3]heptanyl, oxetanyl,phenyl, piperazinyl, piperazinonyl, piperidinyl, pyridinyl,pyrrolidinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydropyranyl, ortriazolyl, each substituted with zero to 4 substituents independentlyselected from F, Cl, —OH, C₁₋₃ alkyl, C₁₋₂ hydroxyalkyl, C₁₋₂ alkoxy,—(CH₂)₁₋₂O(C₁₋₂ alkyl), —NR_(x)R_(x), —C(O)NR_(x)R_(x), and—CH₂S(O)₂(C₁₋₂ alkyl).

One embodiment provides a compound of Formula (I), N-oxide, or a saltthereof wherein A is an aromatic group selected from[1,2,4]triazolo[1,5-a]pyridinyl, imidazo[1,2-a]pyridinyl, imidazolyl,indazolyl, isoquinolinyl, oxadiazolyl, oxazolyl, phenyl, pyrazinyl,pyrazolo[3,4-b]pyridinyl, pyrazolyl, pyridazinyl, pyridinyl,pyrimidinyl, pyrrolyl, quinolinonyl, quinolinyl, quinoxalinyl,tetrahydro-[1,2,4]triazolo[1,5-a]pyrazinyl,tetrahydroimidazo[1,2-a]pyrazinyl, tetrahydroisoquinolinyl,tetrahydrothiazolo[5,4-c]pyridinyl, tetrahydrothieno[2,3-c]pyridinyl,thiadiazolyl, thiazolyl, thiooxadiazolyl, and triazolyl, eachsubstituted with zero to 2 R_(14a) and zero to 3 R_(14b); and G, R₁, R₅,R_(14a), R_(14b), R_(x), R_(y), n, and p are defined in the first aspector the second aspect. Included in this embodiment are compounds in whicheach R_(14a) is independently: (i) H, F, Cl, —OH, C₁₋₅ alkyl, C₁₋₂fluoroalkyl, C₁₋₂ hydroxyalkyl, —(CH₂)₀₋₂OCH₃, —CHR_(x)NR_(x)(C₁₋₅alkyl), —CHR_(x)NR_(x)(C₁₋₂ cyanoalkyl), —CHR_(x)NR_(x)((CH₂)₁₋₂OCH₃),—CHR_(x)N((CH₂)₁₋₂OCH₃)₂, —CH₂NR_(x)(CH₂C≡CR_(x)),—CH₂NR_(x)CH₂CH₂NR_(x)R_(x), —(CH₂)₁₋₃CR_(x)R_(x)NR_(x)R_(x),—CH(NH₂)(CH₂)₃₋₄NR_(x)R_(x), —CH₂NR_(x)(CH₂)₁₋₂O(C₁₋₃ alkyl),—CH₂NR_(x)(CH₂)₁₋₂O(CH₂)₁₋₂OH, —CH₂NH(CH₂)₁₋₂S(O)₂OH,—CH₂C(O)NR_(x)R_(x), —NR_(x)R_(y), —NR_(x)(CH₂)₂₋₃NR_(x)R_(x),—NR_(x)C(O)(C₁₋₂ alkyl), —NR_(x)C(O)(C₁₋₂ fluoroalkyl),—NR_(x)C(O)O(C₁₋₃ alkyl), —NR_(x)C(O)(CH₂)₁₋₂NR_(x)R_(x),—NR_(x)CH₂C(O)CH₂NR_(x)R_(x), —C(O)(C₁₋₂ alkyl), —C(O)CH₂CR_(x)R_(x)OH,—C(O)CH₂NR_(x)R_(x), —C(O)NR_(x)R_(x), —C(O)NR_(x)(CH₂CN),—C(O)NR_(x)(CR_(x)R_(x))₂₋₃NR_(x)R_(x),—C(O)N(CH₂CH₃)(CR_(x)R_(x))₂₋₃NR_(x)R_(x),—C(O)NR_(x)CH₂C(O)NR_(x)R_(x), —C(O)NR_(x)CH₂CH₂NR_(x)C(O)CH₃,—O(CR_(x)R_(x))₂₋₃NR_(x)R_(x), —S(O)₂NR_(x)R_(x), or —C(O)CH₂S(O)₂(C₁₋₂alkyl); (ii) 8-azabicyclo[3.2.1]octanyl, azaspiro[3.5]nonanyl,azetidinyl, benzo[c][1,2,5]oxadiazolyl, cyclopentyl, cyclohexyl,diazepanyl, morpholinyl, phenyl, piperazinyl, piperidinyl, pyrazolyl,pyridinyl, pyrrolidinonyl, quinolinyl, quinuclidinyl,tetrahydroisoquinolinyl, tetrahydropyridinyl, or thiazolidinyl, eachsubstituted with zero to 2 substituents independently selected from C₁₋₄alkyl, C₁₋₂ fluoroalkyl, C₁₋₄ hydroxyalkyl, —NR_(x)R_(x),—(CH₂)₁₋₂NR_(x)R_(x), —C(O)(C₁₋₂ alkyl), —C(O)CH₂NR_(x)R_(x),—C(O)O(C₁₋₃ alkyl), —CH₂C(O)NR_(x)R_(x), C₃₋₆ cycloalkyl, —CH₂(phenyl),—CH₂(pyrrolyl), —CH₂(morpholinyl), —CH₂(methylpiperazinyl),—CH₂(thiophenyl), methylpiperidinyl, isobutylpiperidinyl, and pyridinyl;or (iii) -L₃-R_(14c); each R_(14b) is F, —CH₃, or —OCH₃; and R_(14c) isadamantanyl, azepanyl, azetidinyl, C₃₋₇ cycloalkyl, diazepanyl,imidazolyl, indolyl, morpholinyl, octahydropyrrolo[3,4-c]pyrrolyl,phenyl, piperazinonyl, piperazinyl, piperidinyl, pyridinyl,pyrrolidinonyl, pyrrolidinyl, pyrrolyl, triazolyl, or tetrazolyl, eachsubstituted with zero to 1 substituent selected from F, —OH, C₁₋₄ alkyl,C₁₋₃ hydroxyalkyl, —NR_(x)R_(y), —NR_(x)C(O)CH₃, —C(O)(C₁₋₂ alkyl),—C(O)NR_(x)R_(x), —C(O)N(CH₂CH₃)₂, —C(O)(tetrahydrofuranyl), —C(O)O(C₁₋₂alkyl), —CH₂C(O)NR_(x)R_(y), morpholinyl, methylpiperidinyl, pyrazinyl,pyridinyl, and pyrrolidinyl.

One embodiment provides a compound of Formula (I), N-oxide, or a saltthereof wherein A is:

-   (i) —NR₇R₈ wherein R₇ and R₈ together with the nitrogen atom to    which they are attached form a heterocyclic ring selected from    piperazinyl, piperidinyl, or diazaspiro[3.3]heptanyl, wherein said    heterocyclic ring is substituted with zero to 1 R_(7b) and zero to 1    R_(7c); or-   (ii) —CHR₁₂R₁₃, wherein R₁₂ and R₁₃ together with the carbon atom to    which they are attached form a cyclic group selected from    cyclopentyl, cyclohexyl, morpholinyl, or piperidinyl, each    substituted with zero to 1 R_(12a);    and G, R₁, R₅, R_(7b), R_(7c), R_(12a), and n are defined in the    first aspect or the second aspect.    Included in this embodiment are compounds in which G is:

Also included in this embodiment are compounds in which R₁ is —CH₃ or—CH(CH₃)₂; each R₂ is independently —CH₃ or —OCH₃; and p is zero, 1, or2.

One embodiment provides a compound of Formula (I), N-oxide, or a saltthereof wherein said compound is selected from Examples 1 to 472.

One embodiment provides a compound of Formula (I), N-oxide, or a saltthereof wherein said compound is selected from Examples 1 to 351.

One embodiment provides a compound of Formula (I), N-oxide, or a saltthereof wherein said compound is selected from Examples 352 to 472.

The present invention may be embodied in other specific forms withoutdeparting from the spirit or essential attributes thereof. The inventionencompasses all combinations of the aspects and/or embodiments of theinvention noted herein. It is understood that any and all embodiments ofthe present invention may be taken in conjunction with any otherembodiment or embodiments to describe additional embodiments. It is alsoto be understood that each individual element of the embodiments ismeant to be combined with any and all other elements from any embodimentto describe an additional embodiment.

Definitions

The features and advantages of the invention may be more readilyunderstood by those of ordinary skill in the art upon reading thefollowing detailed description. It is to be appreciated that certainfeatures of the invention that are, for clarity reasons, described aboveand below in the context of separate embodiments, may also be combinedto form a single embodiment. Conversely, various features of theinvention that are, for brevity reasons, described in the context of asingle embodiment, may also be combined so as to form sub-combinationsthereof. Embodiments identified herein as exemplary or preferred areintended to be illustrative and not limiting.

Unless specifically stated otherwise herein, references made in thesingular may also include the plural. For example, “a” and “an” mayrefer to either one, or one or more.

As used herein, the phrase “compounds” refers to at least one compound.For example, a compound of Formula (I) includes a compound of Formula(I) and two or more compounds of Formula (I).

Unless otherwise indicated, any heteroatom with unsatisfied valences isassumed to have hydrogen atoms sufficient to satisfy the valences.

The definitions set forth herein take precedence over definitions setforth in any patent, patent application, and/or patent applicationpublication incorporated herein by reference.

Listed below are definitions of various terms used to describe thepresent invention. These definitions apply to the terms as they are usedthroughout the specification (unless they are otherwise limited inspecific instances) either individually or as part of a larger group.

Throughout the specification, groups and substituents thereof may bechosen by one skilled in the field to provide stable moieties andcompounds.

In accordance with a convention used in the art,

is used in structural formulas herein to depict the bond that is thepoint of attachment of the moiety or substituent to the core or backbonestructure.

The terms “halo” and “halogen,” as used herein, refer to F, Cl, Br, andI.

The term “cyano” refers to the group —CN.

The term “amino” refers to the group —NH₂.

The term “oxo” refers to the group ═O.

The term “alkyl” as used herein, refers to both branched andstraight-chain saturated aliphatic hydrocarbon groups containing, forexample, from 1 to 12 carbon atoms, from 1 to 6 carbon atoms, and from 1to 4 carbon atoms. Examples of alkyl groups include, but are not limitedto, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and i-propyl), butyl(e.g., n-butyl, i-butyl, sec-butyl, and t-butyl), and pentyl (e.g.,n-pentyl, isopentyl, neopentyl), n-hexyl, 2-methylpentyl, 2-ethylbutyl,3-methylpentyl, and 4-methylpentyl. When numbers appear in a subscriptafter the symbol “C”, the subscript defines with more specificity thenumber of carbon atoms that a particular group may contain. For example,“C₁₋₆ alkyl” denotes straight and branched chain alkyl groups with oneto six carbon atoms.

The term “fluoroalkyl” as used herein is intended to include bothbranched and straight-chain saturated aliphatic hydrocarbon groupssubstituted with one or more fluorine atoms. For example, “C₁₋₄fluoroalkyl” is intended to include Cl, C₂, C₃, and C₄ alkyl groupssubstituted with one or more fluorine atoms. Representative examples offluoroalkyl groups include, but are not limited to, —CF₃ and —CH₂CF₃.

The term “cyanoalkyl” includes both branched and straight-chainsaturated alkyl groups substituted with one or more cyano groups. Forexample, “cyanoalkyl” includes —CH₂CN, —CH₂CH₂CN, and C₁₋₄ cyanoalkyl.

The term “aminoalkyl” includes both branched and straight-chainsaturated alkyl groups substituted with one or more amine groups. Forexample, “aminoalkyl” includes —CH₂NH₂, —CH₂CH₂NH₂, and C₁₋₄ aminoalkyl.

The term “hydroxyalkyl” includes both branched and straight-chainsaturated alkyl groups substituted with one or more hydroxyl groups. Forexample, “hydroxyalkyl” includes —CH₂OH, —CH₂CH₂OH, and C₁₋₄hydroxyalkyl.

The term “hydroxy-fluoroalkyl” includes both branched and straight-chainsaturated alkyl groups substituted with one or more hydroxyl groups andone or more fluorine atoms. For example, “hydroxy-fluoroalkyl” includes—CHFCH₂OH, —CH₂CHFC(CH₃)₂OH, and C₁₋₄ hydroxy-fluoroalkyl.

The term “cycloalkyl,” as used herein, refers to a group derived from anon-aromatic monocyclic or polycyclic hydrocarbon molecule by removal ofone hydrogen atom from a saturated ring carbon atom. Representativeexamples of cycloalkyl groups include, but are not limited to,cyclopropyl, cyclopentyl, and cyclohexyl. When numbers appear in asubscript after the symbol “C”, the subscript defines with morespecificity the number of carbon atoms that a particular cycloalkylgroup may contain. For example, “C₃-C₆ cycloalkyl” denotes cycloalkylgroups with three to six carbon atoms.

The term “alkoxy,” as used herein, refers to an alkyl group attached tothe parent molecular moiety through an oxygen atom, for example, methoxygroup (—OCH₃). For example, “C₁₋₃ alkoxy” denotes alkoxy groups with oneto three carbon atoms.

The term “alkoxyalkyl,” as used herein, refers to an alkoxy groupattached through its oxygen atom to an alkyl group, which is attached tothe parent molecular moiety, for example, methoxymethyl group(—CH₂OCH₃). For example, “C₂₋₄ alkoxyalkyl” denotes alkoxyalkyl groupswith two to four carbon atoms, such as —CH₂OCH₃, —CH₂CH₂OCH₃,—CH₂OCH₂CH₃, and —CH₂CH₂OCH₂CH₃.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

The compounds of Formula (I) can be provided as amorphous solids orcrystalline solids. Lyophilization can be employed to provide thecompounds of Formula (I) as amorphous solids.

It should further be understood that solvates (e.g., hydrates) of thecompounds of Formula (I) are also within the scope of the presentinvention. The term “solvate” means a physical association of a compoundof Formula (I) with one or more solvent molecules, whether organic orinorganic. This physical association includes hydrogen bonding. Incertain instances the solvate will be capable of isolation, for examplewhen one or more solvent molecules are incorporated in the crystallattice of the crystalline solid. “Solvate” encompasses bothsolution-phase and isolable solvates. Exemplary solvates includehydrates, ethanolates, methanolates, isopropanolates, acetonitrilesolvates, and ethyl acetate solvates. Methods of solvation are known inthe art.

Various forms of prodrugs are well known in the art and are describedin:

-   a) The Practice of Medicinal Chemistry, Camille G. Wermuth et al.,    Ch 31, (Academic Press, 1996);-   b) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985);-   c) A Textbook of Drug Design and Development, P. Krogsgaard-Larson    and H. Bundgaard, eds. Ch 5, pgs 113-191 (Harwood Academic    Publishers, 1991); and-   d) Hydrolysis in Drug and Prodrug Metabolism, Bernard Testa and    Joachim M. Mayer, (Wiley-VCH, 2003).

In addition, compounds of Formula (I), subsequent to their preparation,can be isolated and purified to obtain a composition containing anamount by weight equal to or greater than 99% of a compound of Formula(I) (“substantially pure”), which is then used or formulated asdescribed herein. Such “substantially pure” compounds of Formula (I) arealso contemplated herein as part of the present invention.

“Stable compound” and “stable structure” are meant to indicate acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and formulation into anefficacious therapeutic agent. The present invention is intended toembody stable compounds.

“Therapeutically effective amount” is intended to include an amount of acompound of the present invention alone or an amount of the combinationof compounds claimed or an amount of a compound of the present inventionin combination with other active ingredients effective to act as aninhibitor to TLR7/8/9, or effective to treat or prevent autoimmuneand/or inflammatory disease states, such as SLE, IBD, multiple sclerosis(MS), and Sjögren's syndrome, and rheumatoid arthritis.

As used herein, “treating” or “treatment” cover the treatment of adisease-state in a mammal, particularly in a human, and include: (a)preventing the disease-state from occurring in a mammal, in particular,when such mammal is predisposed to the disease-state but has not yetbeen diagnosed as having it; (b) inhibiting the disease-state, i.e.,arresting its development; and/or (c) relieving the disease-state, i.e.,causing regression of the disease state.

The compounds of the present invention are intended to include allisotopes of atoms occurring in the present compounds. Isotopes includethose atoms having the same atomic number but different mass numbers. Byway of general example and without limitation, isotopes of hydrogeninclude deuterium (D) and tritium (T). Isotopes of carbon include ¹³Cand ¹⁴C. Isotopically-labeled compounds of the invention can generallybe prepared by conventional techniques known to those skilled in the artor by processes analogous to those described herein, using anappropriate isotopically-labeled reagent in place of the non-labeledreagent otherwise employed. For example, methyl (—CH₃) also includesdeuterated methyl groups such as —CD₃.

Utility

The human immune system has evolved to defend the body frommicro-organisms, viruses, and parasites that can cause infection,disease or death. Complex regulatory mechanisms ensure that the variouscellular components of the immune system target the foreign substancesor organisms, while not causing permanent or significant damage to theindividual. While the initiating events are not well understood at thistime, in autoimmune disease states the immune system directs itsinflammatory response to target organs in the afflicted individual.Different autoimmune diseases are typically characterized by thepredominate or initial target organ or tissues affected; such as thejoint in the case of rheumatoid arthritis, the thyroid gland in the caseof Hashimoto's thyroiditis, the central nervous system in the case ofmultiple sclerosis, the pancreas in the case of type I diabetes, and thebowel in the case of inflammatory bowel disease.

The compounds of the invention inhibit signaling through Toll-likereceptor 7, or 8, or 9 (TLR7, TLR8, TLR9) or combinations thereof.Accordingly, compounds of Formula (I) have utility in treatingconditions associated with the inhibition of signaling through one ormore of TLR7, TLR8, or TLR9. Such conditions include TLR7, TLR8, or TLR9receptor associated diseases in which cytokine levels are modulated as aconsequence of intracellular signaling.

As used herein, the terms “treating” or “treatment” encompass thetreatment of a disease state in a mammal, particularly in a human, andinclude: (a) preventing or delaying the occurrence of the disease statein a mammal, in particular, when such mammal is predisposed to thedisease state but has not yet been diagnosed as having it; (b)inhibiting the disease state, i.e., arresting its development; and/or(c) achieving a full or partial reduction of the symptoms or diseasestate, and/or alleviating, ameliorating, lessening, or curing thedisease or disorder and/or its symptoms.

In view of their activity as selective inhibitors of TLR7, TLR8, orTLR9, compounds of Formula (I) are useful in treating TLR7, TLR8, orTLR9 family receptor associated diseases, but not limited to,inflammatory diseases such as Crohn's disease, ulcerative colitis,asthma, graft versus host disease, allograft rejection, chronicobstructive pulmonary disease; autoimmune diseases such as Graves'disease, rheumatoid arthritis, systemic lupus erythematosus, lupusnephritis, cutaneous lupus, psoriasis; auto-inflammatory diseasesincluding Cryopyrin-Associated Periodic Syndromes (CAPS), TNF ReceptorAssociated Periodic Syndrome (TRAPS), Familial Mediterranean Fever(FMF), adult onset stills, systemic onset juvenile idiopathic arthritis,gout, gouty arthritis; metabolic diseases including type 2 diabetes,atherosclerosis, myocardial infarction; destructive bone disorders suchas bone resorption disease, osteoarthritis, osteoporosis, multiplemyeloma-related bone disorder; proliferative disorders such as acutemyelogenous leukemia, chronic myelogenous leukemia; angiogenic disorderssuch as angiogenic disorders including solid tumors, ocularneovascularization, and infantile haemangiomas; infectious diseases suchas sepsis, septic shock, and Shigellosis; neurodegenerative diseasessuch as Alzheimer's disease, Parkinson's disease, cerebral ischemias orneurodegenerative disease caused by traumatic injury, oncologic andviral diseases such as metastatic melanoma, Kaposi's sarcoma, multiplemyeloma, and HIV infection and CMV retinitis, AIDS, respectively.

More particularly, the specific conditions or diseases that may betreated with the inventive compounds include, without limitation,pancreatitis (acute or chronic), asthma, allergies, adult respiratorydistress syndrome, chronic obstructive pulmonary disease,glomerulonephritis, rheumatoid arthritis, systemic lupus erythematosus,scleroderma, chronic thyroiditis, Graves' disease, autoimmune gastritis,diabetes, autoimmune hemolytic anemia, autoimmune neutropenia,thrombocytopenia, atopic dermatitis, chronic active hepatitis,myasthenia gravis, multiple sclerosis, inflammatory bowel disease,ulcerative colitis, Crohn's disease, psoriasis, graft vs. host disease,inflammatory reaction induced by endotoxin, tuberculosis,atherosclerosis, muscle degeneration, cachexia, psoriatic arthritis,Reiter's syndrome, gout, traumatic arthritis, rubella arthritis, acutesynovitis, pancreatic-cell disease; diseases characterized by massiveneutrophil infiltration; rheumatoid spondylitis, gouty arthritis andother arthritic conditions, cerebral malaria, chronic pulmonaryinflammatory disease, silicosis, pulmonary sarcoidosis, bone resorptiondisease, allograft rejections, fever and myalgias due to infection,cachexia secondary to infection, keloid formation, scar tissueformation, ulcerative colitis, pyresis, influenza, osteoporosis,osteoarthritis, acute myelogenous leukemia, chronic myelogenousleukemia, metastatic melanoma, Kaposi's sarcoma, multiple myeloma,sepsis, septic shock, and Shigellosis; Alzheimer's disease, Parkinson'sdisease, cerebral ischemias or neurodegenerative disease caused bytraumatic injury; angiogenic disorders including solid tumors, ocularneovascularization, and infantile haemangiomas; viral diseases includingacute hepatitis infection (including hepatitis A, hepatitis B andhepatitis C), HIV infection and CMV retinitis, AIDS, ARC or malignancy,and herpes; stroke, myocardial ischemia, ischemia in stroke heartattacks, organ hypoxia, vascular hyperplasia, cardiac and renalreperfusion injury, thrombosis, cardiac hypertrophy, thrombin-inducedplatelet aggregation, endotoxemia and/or toxic shock syndrome,conditions associated with prostaglandin endoperoxidase syndase-2, andpemphigus vulgaris. Included in this embodiment are methods of treatmentin which the condition is selected from lupus including lupus nephritisand systemic lupus erythematosus (SLE), Crohn's disease, ulcerativecolitis, allograft rejection, rheumatoid arthritis, psoriasis,ankylosing spondylitis, psoriatic arthritis, and pemphigus vulgaris.Also included are methods of treatment in which the condition isselected from ischemia reperfusion injury, including cerebral ischemiareperfusions injury arising from stroke and cardiac ischemia reperfusioninjury arising from myocardial infarction. Another method of treatmentis one in which the condition is multiple myeloma.

In one embodiment, the compounds of Formula (I) are useful in treatingcancer, including Waldenstrom's Macroglobulinemia (WM), diffuse large Bcell lymphoma (DLBCL), chronic lymphocytic leukemia (CLL), cutaneousdiffuse large B cell lymphoma, and primary CNS lymphoma.

In addition, the TLR7, TLR8, or TLR9 inhibitors of the present inventioninhibit the expression of inducible pro-inflammatory proteins such asprostaglandin endoperoxide synthase-2 (PGHS-2), also referred to ascyclooxygenase-2 (COX-2), IL-1, IL-6, IL-18, chemokines. Accordingly,additional TLR7/8/9 associated conditions include edema, analgesia,fever and pain, such as neuromuscular pain, headache, pain caused bycancer, dental pain and arthritis pain. The inventive compounds also maybe used to treat veterinary viral infections, such as lentivirusinfections, including, but not limited to equine infectious anemiavirus; or retrovirus infections, including feline immunodeficiencyvirus, bovine immunodeficiency virus, and canine immunodeficiency virus.

The present invention thus provides methods for treating suchconditions, comprising administering to a subject in need thereof atherapeutically-effective amount of at least one compound of Formula (I)or a salt thereof. “Therapeutically effective amount” is intended toinclude an amount of a compound of the present invention that iseffective when administered alone or in combination to inhibitautoimmune disease or chronic inflammatory disease.

The methods of treating TLR7, TLR8, or TLR9 associated conditions maycomprise administering compounds of Formula (I) alone or in combinationwith each other and/or other suitable therapeutic agents useful intreating such conditions. Accordingly, “therapeutically effectiveamount” is also intended to include an amount of the combination ofcompounds claimed that is effective to inhibit TLR7, TLR8, or TLR9and/or treat diseases associated with TLR7, TLR8, or TLR9.

Exemplary of such other therapeutic agents include corticosteroids,rolipram, calphostin, cytokine-suppressive anti-inflammatory drugs(CSAIDs), Interleukin-10, glucocorticoids, salicylates, nitric oxide,and other immunosuppressants; nuclear translocation inhibitors, such asdeoxyspergualin (DSG); non-steroidal anti-inflammatory drugs (NSAIDs)such as ibuprofen, celecoxib and rofecoxib; steroids such as prednisoneor dexamethasone; antiviral agents such as abacavir; antiproliferativeagents such as methotrexate, leflunomide, FK506 (tacrolimus, PROGRAF@);anti-malarials such as hydroxychloroquine; cytotoxic drugs such asazathiprine and cyclophosphamide; TNF-α inhibitors such as tenidap,anti-TNF antibodies or soluble TNF receptor, and rapamycin (sirolimus orRAPAMUNE®) or derivatives thereof.

The above other therapeutic agents, when employed in combination withthe compounds of the present invention, may be used, for example, inthose amounts indicated in the Physicians' Desk Reference (PDR) or asotherwise determined by one of ordinary skill in the art. In the methodsof the present invention, such other therapeutic agent(s) may beadministered prior to, simultaneously with, or following theadministration of the inventive compounds. The present invention alsoprovides pharmaceutical compositions capable of treating TLR7/8/9receptor-associated conditions, including IL-1 family receptor-mediateddiseases as described above.

The inventive compositions may contain other therapeutic agents asdescribed above and may be formulated, for example, by employingconventional solid or liquid vehicles or diluents, as well aspharmaceutical additives of a type appropriate to the mode of desiredadministration (e.g., excipients, binders, preservatives, stabilizers,flavors, etc.) according to techniques such as those well known in theart of pharmaceutical formulation.

Accordingly, the present invention further includes compositionscomprising one or more compounds of Formula (I) and a pharmaceuticallyacceptable carrier.

A “pharmaceutically acceptable carrier” refers to media generallyaccepted in the art for the delivery of biologically active agents toanimals, in particular, mammals. Pharmaceutically acceptable carriersare formulated according to a number of factors well within the purviewof those of ordinary skill in the art. These include without limitationthe type and nature of the active agent being formulated; the subject towhich the agent-containing composition is to be administered; theintended route of administration of the composition; and, thetherapeutic indication being targeted. Pharmaceutically acceptablecarriers include both aqueous and non-aqueous liquid media, as well as avariety of solid and semi-solid dosage forms. Such carriers can includea number of different ingredients and additives in addition to theactive agent, such additional ingredients being included in theformulation for a variety of reasons, e.g., stabilization of the activeagent, binders, etc., well known to those of ordinary skill in the art.Descriptions of suitable pharmaceutically acceptable carriers, andfactors involved in their selection, are found in a variety of readilyavailable sources such as, for example, Remington's PharmaceuticalSciences, 17th Edition (1985), which is incorporated herein by referencein its entirety.

Compounds in accordance with Formula (I) can be administered by anymeans suitable for the condition to be treated, which can depend on theneed for site-specific treatment or quantity of Formula (I) compound tobe delivered.

Also embraced within this invention is a class of pharmaceuticalcompositions comprising a compound of Formula (I) and one or morenon-toxic, pharmaceutically-acceptable carriers and/or diluents and/oradjuvants (collectively referred to herein as “carrier” materials) and,if desired, other active ingredients. The compounds of Formula (I) maybe administered by any suitable route, preferably in the form of apharmaceutical composition adapted to such a route, and in a doseeffective for the treatment intended. The compounds and compositions ofthe present invention may, for example, be administered orally,mucosally, or parenterally including intravascularly, intravenously,intraperitoneally, subcutaneously, intramuscularly, and intrasternallyin dosage unit formulations containing conventional pharmaceuticallyacceptable carriers, adjuvants, and vehicles. For example, thepharmaceutical carrier may contain a mixture of mannitol or lactose andmicrocrystalline cellulose. The mixture may contain additionalcomponents such as a lubricating agent, e.g. magnesium stearate and adisintegrating agent such as crospovidone. The carrier mixture may befilled into a gelatin capsule or compressed as a tablet. Thepharmaceutical composition may be administered as an oral dosage form oran infusion, for example.

For oral administration, the pharmaceutical composition may be in theform of, for example, a tablet, capsule, liquid capsule, suspension, orliquid. The pharmaceutical composition is preferably made in the form ofa dosage unit containing a particular amount of the active ingredient.For example, the pharmaceutical composition may be provided as a tabletor capsule comprising an amount of active ingredient in the range offrom about 0.1 to 1000 mg, preferably from about 0.25 to 250 mg, andmore preferably from about 0.5 to 100 mg. A suitable daily dose for ahuman or other mammal may vary widely depending on the condition of thepatient and other factors, but, can be determined using routine methods.

Any pharmaceutical composition contemplated herein can, for example, bedelivered orally via any acceptable and suitable oral preparations.Exemplary oral preparations, include, but are not limited to, forexample, tablets, troches, lozenges, aqueous and oily suspensions,dispersible powders or granules, emulsions, hard and soft capsules,liquid capsules, syrups, and elixirs. Pharmaceutical compositionsintended for oral administration can be prepared according to anymethods known in the art for manufacturing pharmaceutical compositionsintended for oral administration. In order to provide pharmaceuticallypalatable preparations, a pharmaceutical composition in accordance withthe invention can contain at least one agent selected from sweeteningagents, flavoring agents, coloring agents, demulcents, antioxidants, andpreserving agents.

A tablet can, for example, be prepared by admixing at least one compoundof Formula (I) with at least one non-toxic pharmaceutically acceptableexcipient suitable for the manufacture of tablets. Exemplary excipientsinclude, but are not limited to, for example, inert diluents, such as,for example, calcium carbonate, sodium carbonate, lactose, calciumphosphate, and sodium phosphate; granulating and disintegrating agents,such as, for example, microcrystalline cellulose, sodiumcrosscarmellose, corn starch, and alginic acid; binding agents, such as,for example, starch, gelatin, polyvinyl-pyrrolidone, and acacia; andlubricating agents, such as, for example, magnesium stearate, stearicacid, and talc. Additionally, a tablet can either be uncoated, or coatedby known techniques to either mask the bad taste of an unpleasanttasting drug, or delay disintegration and absorption of the activeingredient in the gastrointestinal tract thereby sustaining the effectsof the active ingredient for a longer period. Exemplary water solubletaste masking materials, include, but are not limited to,hydroxypropyl-methylcellulose and hydroxypropyl-cellulose. Exemplarytime delay materials, include, but are not limited to, ethyl celluloseand cellulose acetate butyrate.

Hard gelatin capsules can, for example, be prepared by mixing at leastone compound of Formula (I) with at least one inert solid diluent, suchas, for example, calcium carbonate; calcium phosphate; and kaolin.

Soft gelatin capsules can, for example, be prepared by mixing at leastone compound of Formula (I) with at least one water soluble carrier,such as, for example, polyethylene glycol; and at least one oil medium,such as, for example, peanut oil, liquid paraffin, and olive oil.

An aqueous suspension can be prepared, for example, by admixing at leastone compound of Formula (I) with at least one excipient suitable for themanufacture of an aqueous suspension. Exemplary excipients suitable forthe manufacture of an aqueous suspension, include, but are not limitedto, for example, suspending agents, such as, for example, sodiumcarboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose,sodium alginate, alginic acid, polyvinyl-pyrrolidone, gum tragacanth,and gum acacia; dispersing or wetting agents, such as, for example, anaturally-occurring phosphatide, e.g., lecithin; condensation productsof alkylene oxide with fatty acids, such as, for example,polyoxyethylene stearate; condensation products of ethylene oxide withlong chain aliphatic alcohols, such as, for exampleheptadecaethylene-oxycetanol; condensation products of ethylene oxidewith partial esters derived from fatty acids and hexitol, such as, forexample, polyoxyethylene sorbitol monooleate; and condensation productsof ethylene oxide with partial esters derived from fatty acids andhexitol anhydrides, such as, for example, polyethylene sorbitanmonooleate. An aqueous suspension can also contain at least onepreservative, such as, for example, ethyl and n-propylp-hydroxybenzoate; at least one coloring agent; at least one flavoringagent; and/or at least one sweetening agent, including but not limitedto, for example, sucrose, saccharin, and aspartame.

Oily suspensions can, for example, be prepared by suspending at leastone compound of Formula (I) in either a vegetable oil, such as, forexample, arachis oil; olive oil; sesame oil; and coconut oil; or inmineral oil, such as, for example, liquid paraffin.

An oily suspension can also contain at least one thickening agent, suchas, for example, beeswax; hard paraffin; and cetyl alcohol. In order toprovide a palatable oily suspension, at least one of the sweeteningagents already described hereinabove, and/or at least one flavoringagent can be added to the oily suspension. An oily suspension canfurther contain at least one preservative, including, but not limitedto, for example, an anti-oxidant, such as, for example, butylatedhydroxyanisol, and alpha-tocopherol.

Dispersible powders and granules can, for example, be prepared byadmixing at least one compound of Formula (I) with at least onedispersing and/or wetting agent; at least one suspending agent; and/orat least one preservative. Suitable dispersing agents, wetting agents,and suspending agents are as already described above. Exemplarypreservatives include, but are not limited to, for example,anti-oxidants, e.g., ascorbic acid. In addition, dispersible powders andgranules can also contain at least one excipient, including, but notlimited to, for example, sweetening agents; flavoring agents; andcoloring agents.

An emulsion of at least one compound of Formula (I) thereof can, forexample, be prepared as an oil-in-water emulsion. The oily phase of theemulsions comprising compounds of Formula (I) may be constituted fromknown ingredients in a known manner. The oil phase can be provided by,but is not limited to, for example, a vegetable oil, such as, forexample, olive oil and arachis oil; a mineral oil, such as, for example,liquid paraffin; and mixtures thereof. While the phase may comprisemerely an emulsifier, it may comprise a mixture of at least oneemulsifier with a fat or an oil or with both a fat and an oil. Suitableemulsifying agents include, but are not limited to, for example,naturally-occurring phosphatides, e.g., soy bean lecithin; esters orpartial esters derived from fatty acids and hexitol anhydrides, such as,for example, sorbitan monooleate; and condensation products of partialesters with ethylene oxide, such as, for example, polyoxyethylenesorbitan monooleate. Preferably, a hydrophilic emulsifier is includedtogether with a lipophilic emulsifier which acts as a stabilizer. It isalso preferred to include both an oil and a fat. Together, theemulsifier(s) with or without stabilizer(s) make-up the so-calledemulsifying wax, and the wax together with the oil and fat make up theso-called emulsifying ointment base which forms the oily dispersed phaseof the cream formulations. An emulsion can also contain a sweeteningagent, a flavoring agent, a preservative, and/or an antioxidant.Emulsifiers and emulsion stabilizers suitable for use in the formulationof the present invention include Tween 60, Span 80, cetostearyl alcohol,myristyl alcohol, glyceryl monostearate, sodium lauryl sulfate, glyceryldistearate alone or with a wax, or other materials well known in theart.

The compounds of Formula (I) can, for example, also be deliveredintravenously, subcutaneously, and/or intramuscularly via anypharmaceutically acceptable and suitable injectable form. Exemplaryinjectable forms include, but are not limited to, for example, sterileaqueous solutions comprising acceptable vehicles and solvents, such as,for example, water, Ringer's solution, and isotonic sodium chloridesolution; sterile oil-in-water microemulsions; and aqueous or oleaginoussuspensions.

Formulations for parenteral administration may be in the form of aqueousor non-aqueous isotonic sterile injection solutions or suspensions.These solutions and suspensions may be prepared from sterile powders orgranules using one or more of the carriers or diluents mentioned for usein the formulations for oral administration or by using other suitabledispersing or wetting agents and suspending agents. The compounds may bedissolved in water, polyethylene glycol, propylene glycol, ethanol, cornoil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodiumchloride, tragacanth gum, and/or various buffers. Other adjuvants andmodes of administration are well and widely known in the pharmaceuticalart. The active ingredient may also be administered by injection as acomposition with suitable carriers including saline, dextrose, or water,or with cyclodextrin (i.e. Captisol), cosolvent solubilization (i.e.propylene glycol) or micellar solubilization (i.e. Tween 80).

The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally acceptable diluent orsolvent, for example as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution, and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employed,including synthetic mono- or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

A sterile injectable oil-in-water microemulsion can, for example, beprepared by 1) dissolving at least one compound of Formula (I) in anoily phase, such as, for example, a mixture of soybean oil and lecithin;2) combining the Formula (I) containing oil phase with a water andglycerol mixture; and 3) processing the combination to form amicroemulsion.

A sterile aqueous or oleaginous suspension can be prepared in accordancewith methods already known in the art. For example, a sterile aqueoussolution or suspension can be prepared with a non-toxicparenterally-acceptable diluent or solvent, such as, for example,1,3-butane diol; and a sterile oleaginous suspension can be preparedwith a sterile non-toxic acceptable solvent or suspending medium, suchas, for example, sterile fixed oils, e.g., synthetic mono- ordiglycerides; and fatty acids, such as, for example, oleic acid.

Pharmaceutically acceptable carriers, adjuvants, and vehicles that maybe used in the pharmaceutical compositions of this invention include,but are not limited to, ion exchangers, alumina, aluminum stearate,lecithin, self-emulsifying drug delivery systems (SEDDS) such asd-alpha-tocopherol polyethyleneglycol 1000 succinate, surfactants usedin pharmaceutical dosage forms such as Tweens, polyethoxylated castoroil such as CREMOPHOR surfactant (BASF), or other similar polymericdelivery matrices, serum proteins, such as human serum albumin, buffersubstances such as phosphates, glycine, sorbic acid, potassium sorbate,partial glyceride mixtures of saturated vegetable fatty acids, water,salts or electrolytes, such as protamine sulfate, disodium hydrogenphosphate, potassium hydrogen phosphate, sodium chloride, zinc salts,colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone,cellulose-based substances, polyethylene glycol, sodiumcarboxymethylcellulose, polyacrylates, waxes,polyethylene-polyoxypropylene-block polymers, polyethylene glycol andwool fat. Cyclodextrins such as alpha-, beta-, and gamma-cyclodextrin,or chemically modified derivatives such as hydroxyalkylcyclodextrins,including 2- and 3-hydroxypropyl-cyclodextrins, or other solubilizedderivatives may also be advantageously used to enhance delivery ofcompounds of the formulae described herein.

The pharmaceutically active compounds of this invention can be processedin accordance with conventional methods of pharmacy to produce medicinalagents for administration to patients, including humans and othermammals. The pharmaceutical compositions may be subjected toconventional pharmaceutical operations such as sterilization and/or maycontain conventional adjuvants, such as preservatives, stabilizers,wetting agents, emulsifiers, buffers etc. Tablets and pills canadditionally be prepared with enteric coatings. Such compositions mayalso comprise adjuvants, such as wetting, sweetening, flavoring, andperfuming agents.

The amounts of compounds that are administered and the dosage regimenfor treating a disease condition with the compounds and/or compositionsof this invention depends on a variety of factors, including the age,weight, sex, the medical condition of the subject, the type of disease,the severity of the disease, the route and frequency of administration,and the particular compound employed. Thus, the dosage regimen may varywidely, but can be determined routinely using standard methods. A dailydose of about 0.001 to 100 mg/kg body weight, preferably between about0.0025 and about 50 mg/kg body weight and most preferably between about0.005 to 10 mg/kg body weight, may be appropriate. The daily dose can beadministered in one to four doses per day. Other dosing schedulesinclude one dose per week and one dose per two day cycle.

For therapeutic purposes, the active compounds of this invention areordinarily combined with one or more adjuvants appropriate to theindicated route of administration. If administered orally, the compoundsmay be admixed with lactose, sucrose, starch powder, cellulose esters ofalkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesiumstearate, magnesium oxide, sodium and calcium salts of phosphoric andsulfuric acids, gelatin, acacia gum, sodium alginate,polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted orencapsulated for convenient administration. Such capsules or tablets maycontain a controlled-release formulation as may be provided in adispersion of active compound in hydroxypropylmethyl cellulose.

Pharmaceutical compositions of this invention comprise at least onecompound of Formula (I) and optionally an additional agent selected fromany pharmaceutically acceptable carrier, adjuvant, and vehicle.Alternate compositions of this invention comprise a compound of theFormula (I) described herein, or a prodrug thereof, and apharmaceutically acceptable carrier, adjuvant, or vehicle.

The present invention also encompasses an article of manufacture. Asused herein, article of manufacture is intended to include, but not belimited to, kits and packages. The article of manufacture of the presentinvention, comprises: (a) a first container; (b) a pharmaceuticalcomposition located within the first container, wherein the composition,comprises: a first therapeutic agent, comprising: a compound of thepresent invention or a pharmaceutically acceptable salt form thereof,and (c) a package insert stating that the pharmaceutical composition canbe used for the treatment of an inflammatory disorder and/or anautoimmune disease (as defined previously). In another embodiment, thepackage insert states that the pharmaceutical composition can be used incombination (as defined previously) with a second therapeutic agent totreat an inflammatory disorder and/or an autoimmune disease. The articleof manufacture can further comprise: (d) a second container, whereincomponents (a) and (b) are located within the second container andcomponent (c) is located within or outside of the second container.Located within the first and second containers means that the respectivecontainer holds the item within its boundaries.

The first container is a receptacle used to hold a pharmaceuticalcomposition. This container can be for manufacturing, storing, shipping,and/or individual/bulk selling. First container is intended to cover abottle, jar, vial, flask, syringe, tube (e.g., for a cream preparation),or any other container used to manufacture, hold, store, or distribute apharmaceutical product.

The second container is one used to hold the first container and,optionally, the package insert. Examples of the second containerinclude, but are not limited to, boxes (e.g., cardboard or plastic),crates, cartons, bags (e.g., paper or plastic bags), pouches, and sacks.The package insert can be physically attached to the outside of thefirst container via tape, glue, staple, or another method of attachment,or it can rest inside the second container without any physical means ofattachment to the first container. Alternatively, the package insert islocated on the outside of the second container. When located on theoutside of the second container, it is preferable that the packageinsert is physically attached via tape, glue, staple, or another methodof attachment. Alternatively, it can be adjacent to or touching theoutside of the second container without being physically attached.

The package insert is a label, tag, marker, etc. that recitesinformation relating to the pharmaceutical composition located withinthe first container. The information recited will usually be determinedby the regulatory agency governing the area in which the article ofmanufacture is to be sold (e.g., the United States Food and DrugAdministration). In one embodiment, the package insert specificallyrecites the indications for which the pharmaceutical composition hasbeen approved. The package insert may be made of any material on which aperson can read information contained therein or thereon. For example,the package insert is a printable material (e.g., paper, plastic,cardboard, foil, adhesive-backed paper or plastic, etc.) on which thedesired information has been formed (e.g., printed or applied).

Methods of Preparation

The compounds of the present invention can be prepared in a number ofways well known to one skilled in the art of organic synthesis. Thecompounds of the present invention can be synthesized using the methodsdescribed below, together with synthetic methods known in the art ofsynthetic organic chemistry, or variations thereon as appreciated bythose skilled in the art. Preferred methods include, but are not limitedto, those described below. All references cited herein are herebyincorporated in their entirety by reference.

The compounds of this invention may be prepared using the reactions andtechniques described in this section. The reactions are performed insolvents appropriate to the reagents and materials employed and aresuitable for the transformations being effected. Also, in thedescription of the synthetic methods described below, it is to beunderstood that all proposed reaction conditions, including choice ofsolvent, reaction atmosphere, reaction temperature, duration of theexperiment and work up procedures, are chosen to be the conditionsstandard for that reaction, which should be readily recognized by oneskilled in the art. It is understood by one skilled in the art oforganic synthesis that the functionality present on various portions ofthe molecule must be compatible with the reagents and reactionsproposed. Such restrictions to the substituents that are compatible withthe reaction conditions will be readily apparent to one skilled in theart and alternate methods must then be used. This will sometimes requirea judgment to modify the order of the synthetic steps or to select oneparticular process scheme over another in order to obtain a desiredcompound of the invention. It will also be recognized that another majorconsideration in the planning of any synthetic route in this field isthe judicious choice of the protecting group used for protection of thereactive functional groups present in the compounds described in thisinvention. An authoritative account describing the many alternatives tothe trained practitioner is Greene and Wuts (Protective Groups InOrganic Synthesis, Third Edition, Wiley and Sons, 1999).

EXAMPLES

Preparation of compounds of Formula (I), and intermediates used in thepreparation of compounds of Formula (I), can be prepared usingprocedures shown in the following Examples and related procedures. Themethods and conditions used in these examples, and the actual compoundsprepared in these Examples, are not meant to be limiting, but are meantto demonstrate how the compounds of Formula (I) can be prepared.Starting materials and reagents used in these examples, when notprepared by a procedure described herein, are generally eithercommercially available, or are reported in the chemical literature, ormay be prepared by using procedures described in the chemicalliterature.

Abbreviations

-   Ac acetyl-   ACN acetonitrile-   AcOH acetic acid-   anhyd. anhydrous-   aq. aqueous-   Bn benzyl-   Bu butyl-   Boc tert-butoxycarbonyl-   CV Column Volumes-   DCE dichloroethane-   DCM dichloromethane-   DMAP dimethylaminopyridine-   DMF dimethylformamide-   DMSO dimethylsulfoxide-   EDC 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride-   EtOAc ethyl acetate-   Et ethyl-   EtOH ethanol-   H or H2 hydrogen-   h, hr or hrs hour(s)-   HCTU O-(6-Chlorobenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium    hexafluorophosphate-   hex hexane-   i iso-   IPA isopropyl alcohol-   HOAc acetic acid-   HCl hydrochloric acid-   HPLC high pressure liquid chromatography-   LC liquid chromatography-   M molar-   mM millimolar-   Me methyl-   MeOH methanol-   MHz megahertz-   min. minute(s)-   mins minute(s)-   M⁺¹ (M+H)⁺-   MS mass spectrometry-   n or N normal-   NBS n-bromosuccinimide-   nm nanometer-   nM nanomolar-   NMP N-methylpyrrolidine-   Pd/C palladium on carbon-   PdCl₂(dppf)_(2 [1,1)′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)-   Pd(PPh₃)₄ tetrakis(triphenylphosphine)palladium-   Ph phenyl-   PPh₃ triphenylphosphine-   Pr propyl-   PSI pounds per square inch-   PyBOP bromotripyrrolidinophosphonium hexafluorophosphate-   Ret Time retention time-   sat. saturated-   SFC supercritical fluid chromatography-   TEA triethylamine-   TFA trifluoroacetic acid-   THF tetrahydrofuran

Analytical and Preparative HPLC Conditions:

QC-ACN-AA-XB: Column: Waters Acquity UPLC BEH C18, 2.1×50 mm, 1.7 μmparticles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammoniumacetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammoniumacetate; Temperature: 50° C.; Gradient: 0-100% B over 3 minutes, then a0.75 minute hold at 100% B; Flow: 1.0 mL/min; Detection: UV at 220 nm.QC-ACN-TFA-XB: Column: Waters Acquity UPLC BEH C18, 2.1×50 mm, 1.7 μmparticles; Mobile Phase A: 5:95 acetonitrile:water with 0.1%trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1%trifluoroacetic acid; Temperature: 50° C.; Gradient: 0-100% B over 3minutes, then a 0.75 minute hold at 100% B; Flow: 1.0 mL/min; Detection:UV at 220 nm.Method A1: L3 Acquity: Column: (LCMS) UPLC BEH C18, 2.1×50 mm, 1.7 μmparticles; Mobile Phase: (A) water; (B) acetonitrile; Buffer: 0.05% TFA;Gradient Range: 2%-98% B (0 to 1 min) 98% B (to 1.5 min) 98%-2% B (to1.6 min); Gradient Time: 1.6 min; Flow Rate: 0.8 mL/min; Analysis Time:2.2 min; Detection: Detector 1: UV at 220 nm; Detector 2: MS (ESI⁺).Method B1: L2 Aquity; Column: (LCMS) UPLC BEH C18, 2.1×50 mm, 1.7 μmparticles; Mobile Phase: (A) water; (B) acetonitrile; Buffer: 0.05% TFA;Gradient Range: 2%-98% B (0 to 1 min), 98%-2% B (to 1.5 min); GradientTime: 1.8 min; Flow Rate: 0.8 mL/min; Analysis Time: 2.2 min; Detection:Detector 1: UV at 220 nm; Detector 2: MS (ESI⁺).Method C₁ SCP: Column: Waters Acquity UPLC BEH C18, 2.1×50 mm, 1.7 μmparticles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammoniumacetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammoniumacetate. Temperature: 50° C.; Gradient: 0-100% B over 3 minutes, then a0.75 minute hold at 100% B; Flow: 1.11 mL/min; Detection: UV at 220 nm.Method D1 SCP: Column: Waters Acquity UPLC BEH C18, 2.1×50 mm, 1.7 μmparticles; Mobile Phase A: 5:95 acetonitrile:water with 0.1%trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1%trifluoroacetic acid; Temperature: 50° C.; Gradient: 0-100% B over 3minutes, then a 0.75-minute hold at 100% B; Flow: 1.11 m/min; Detection:UV at 220 nm.Method D2 SCP: Column: XBridge C18, 19×200 mm, 5 μm particles; MobilePhase A: 5:95 acetonitrile: water with 10-mM ammonium acetate; MobilePhase B: 95:5 acetonitrile: water with 10 mM ammonium acetate; Gradient:10-50% B over 20 minutes, then a 5 minute hold at 100% B; Flow: 20mL/min. Detection: UV at 220 nm.Method D3 SCP: Column: XBridge C18, 19×200 mm, 5 μm particles; MobilePhase A: 5:95 acetonitrile: water with 0.1% trifluoroacetic acid; MobilePhase B: 95:5 acetonitrile: water with 0.1% trifluoroacetic acid;Gradient: 6-46% B over 20 minutes, then a 4 minute hold at 100% B; Flow:20 mL/min. Detection: UV at 220 nm.Method E1 iPAC: Column: Waters Xbridge C18 4.6×50 mm 5 m particles;Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate;Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate.Temperature: 50° C.; Gradient: 0-100% B over 1 minute; Flow: 4 mL/min;Detection: UV at 220 nm.

Method F1 iPAC: Column: Waters Acquity BEH C18 2.1×50 mm 1.7 μmparticles;

Mobile Phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid;Mobile Phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid;Temperature: 50° C.; Gradient: 0-100% B over 2.20 minutes; Flow: 0.800mL/min; Detection: UV at 220 nm.(A): Column-Ascentis Express C18 (50×2.1 mm-2.7 μm) Mphase A: 10 mMNH₄COOH in water:ACN (98:02); Mphase B: 10 mM NH₄COOH in water:ACN(02:98), Gradient: 0-100% B over 3 minutes, Flow=1 mL/min.(B): Waters Acquity BEH C18 (2.1×50 mm) 1.7 micron; Buffer: 5 mMammonium acetate pH 5 adjusted with HCOOH, Solvent A: Buffer:ACN (95:5),Solvent B: Buffer:ACN (5:95), Method:% B: 0 min-5%: 1.1 min-95%: 1.7min-95%, Flow: 0.8 mL/min.(C): Column-Ascentis Express C18 (50×2.1 mm, 2.7 μm) Mobile phase A:0.1% HCOOH in water; Mobile phase B: ACN. Temperature: 50° C.; Gradient:0-100% B over 3 minutes; Flow rate: 1.0 mL/min.(D): Kinetex XB-C18 (75×3 mm) 2.6 micron; Solvent A: 10 mM ammoniumformate in water: acetonitrile (98:02); Mobile Phase B: 10 mM ammoniumformate in water: acetonitrile (02:98); Temperature: 50° C.; Gradient:0-100% B over 3 minutes; Flow rate: 1.1 mL/min; Detection: UV at 220 nm.(E): Column: Ascentis Express C18 (50×2.1 mm, 2.7 μm; Mobile Phase A:5:95 acetonitrile: water with 10 mM NH₄₀Ac; Mobile Phase B: 95:5acetonitrile: water with 10 mM NH₄₀Ac; Temperature: 50° C.; Gradient:0-100% B over 3 minutes; Flow: 1.1 mL/min.(F): Column: Ascentis Express C18 (50×2.1) mm, 2.7 μm; Mobile Phase A:5:95 acetonitrile: water with 0.1% TFA; Mobile Phase B: 95:5acetonitrile: water with 0.1% TFA; Temperature: 50° C.; Gradient: 0-100%B over 3 minutes; Flow: 1.1 mL/min.(G): Column: Waters Acquity UPLC BEH C18 (2.1×50 mm), 1.7 micron;Solvent A=100% water with 0.05% TFA; Solvent B=100% acetonitrile with0.05% TFA; gradient=2-98% B over 1 minute, then a 0.5 minute hold at 98%B; Flow rate: 0.8 mL/min; Detection: UV at 220 nm.(H): Column: Acentis Express C18 (50×2.1 mm) 1.7 μm, Acentis C₈ NH₄COOH5 min. M, Mobile Phase A: 10 mM ammonium formate: ACN (98:2), MobilePhase B: 10 mM ammonium formate: ACN (2:98), gradient: 20%-100% B (0-4min); 100% B (4-4.6 min); Flow: 1 mL/min(I) Column: Sunfire C18 (4.6×150) mm, 3.5 μm; Mobile Phase A: 5:95acetonitrile: water with 0.05% TFA; Mobile Phase B: 95:5 acetonitrile:water with 0.05% TFA; Temperature: 50° C.; Gradient: 10-100% B over 12minutes; Flow: 1 mL/min.(J) Column: Sunfire C18 (4.6×150) mm, 3.5 μm; Mobile Phase A: 5:95acetonitrile: water with 0.05% TFA; Mobile Phase B: 95:5 acetonitrile:water with 0.05% TFA;(K) Waters Acquity SDS Mobile Phase: A: water B:ACN; 5%-95% B in 1 min;Gradient Range: 50%-98% B (0-0.5 min); 98% B (0.5 min-1 min); 98%-2% B(1-1.1 min); Run time: 1.2 min; Flow Rate: 0.7 mL/min; Analysis Time:1.7 min; Detection: Detector 1: UV at 220 nm; Detector 2: MS (ES⁺).(L) Acquity UPLC BEH C18 (3.0×50 mm) 1.7 μm. Buffer: 5 mM ammoniumacetate Mobile phase A: Buffer:ACN (95:5); Mobile phase B:Buffer:ACN(5:95) Method: % B: 0 min-20%:1.1 min-90%:1.7 min-90%. Run time: 2.25min; Flow Rate: 0.7 mL/min; Detection: Detector 1: UV at 220 nm;Detector 2: MS (ES⁺).(M): Kinetex SBC18 (4.6×50 mm) 5 micron; Solvent A: 10 mM ammoniumformate in water: acetonitrile (98:02); Mobile Phase B: 10 mM ammoniumformate in water: acetonitrile (02:98); Temperature: 50° C.; Gradient:30-100% B (0-4 min), 100% B (4-4.6 min), 100-30% B (4.6-4.7 min), 30% B(4.7-5.0 min); Flow rate: 1.5 mL/min; Detection: UV at 220 nm.(N): Column-Ascentis Express C18 (50×2.1 mm-2.7 μm) Mphase A: 10 mMNH₄COOH in water:ACN (98:02); Mphase B: 10 mM NH₄COOH in water:ACN(02:98), Gradient: 0-100% B (0-1.7 minutes); 100% B (1.7-3.4 minutes).Flow=1 mL/min.(O) Waters Acquity SDS Column BEH C18 (2.1×50 mm) 1.7 μm. Phase A:buffer in water; Mphase B: buffer in ACN, Gradient: 20-98% B (0-1.25minutes); 98% B (1.25-1.70 minutes); 98%-2% B (1.70-1.75 minutes);Flow=0.8 mL/min.(Q): Column: XBridge BEH XP C18 (50×2.1) mm, 2.5 μm; Mobile Phase A:5:95 acetonitrile: water with 0.1% TFA; Mobile Phase B: 95:5acetonitrile: water with 0.1% TFA; Temperature: 50° C.; Gradient: 0-100%B over 3 minutes; Flow: 1.1 mL/min. (TS): Column: Waters Acquity UPLCBEH C18 (2.1×50 mm), 1.7 micron; Solvent A=100% water with 0.05% TFA;Solvent B=100% acetonitrile with 0.05% TFA; gradient=2-98% B over 1minute, then a 0.5-minute hold at 98% B; Flow rate: 0.8 mL/min;Detection: UV at 254 nm.

Example 16-(3-isopropyl-4-methyl-5-(piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl)-8-methoxy-[1,2,4]triazolo[1,5-a]pyridine

Intermediate 1A: 3-bromo-4-methyl-5-nitropyridin-2-ol

To a solution of 4-methyl-5-nitropyridin-2-ol (4.0 g, 26.0 mmol) inacetic acid (40 mL) was added bromine (1.604 mL, 31.1 mmol) dropwise at0° C. The reaction mixture was stirred for 3 h at room temperature. Thereaction mass was concentrated, ice cold water was added to the residue,the mixture was stirred for 5 min and filtered to afford3-bromo-4-methyl-5-nitropyridin-2-ol (5.2 g, 22.32 mmol, 86% yield) asan off-white solid. LCMS retention time 1.082 min [D]. MS m/z: 235[M+2H]⁺.

Intermediate 1B: 3-bromo-2-chloro-4-methyl-5-nitropyridine

To a solution of 3-bromo-4-methyl-5-nitropyridin-2-ol (5.2 g, 22.32mmol) in acetonitrile (50 mL) were added POCl₃ (20.80 mL, 223 mmol) andDIPEA (3.90 mL, 22.32 mmol) at 0° C. The reaction mixture was stirredfor 3 h at 80° C. The reaction mass was concentrated, ice cold water andsolid NaHCO₃ were added to the residue, extracted with EtOAc (2×50 mL),the organic layer was washed with brine solution, dried over Na₂SO₄,concentrated and purified over 40 g silica column, the compound waseluted in 15% EA in hexane, the fractions were collected andconcentrated to afford 3-bromo-2-chloro-4-methyl-5-nitropyridine (0.48g, 1.909 mmol, 89% yield) as an off-white solid. LCMS retention time2.619 min [D]. MS m/z: 248.9 [M−2H]⁺.

Intermediate 1C:(E)-2-(3-bromo-2-chloro-5-nitropyridin-4-yl)-N,N-dimethylethene-1-amine

A solution of 3-bromo-2-chloro-4-methyl-5-nitropyridine (8.7 g, 34.6mmol) in DMF-DMA (46.3 mL, 346 mmol) was stirred for 16 h at 45° C. Thereaction mass was concentrated under high vacuum, then purified oversilica gel column, the compound was eluted in 30% EA in hexanes, thefractions were collected and concentrated to afford(E)-2-(3-bromo-2-chloro-5-nitropyridin-4-yl)-N,N-dimethylethenamine(10.0 g, 32.6 mmol, 94% yield) as a brown solid. LCMS retention time2.685 min [D]. MS m/z: 306.0 [M+2H]⁺.

Intermediate 1D: 4-bromo-5-chloro-1H-pyrrolo[2,3-c]pyridine

To a solution of(E)-2-(3-bromo-2-chloro-5-nitropyridin-4-yl)-N,N-dimethylethenamine (4.2g, 13.70 mmol) in acetic acid (40 mL) was added iron (3.83 g, 68.5 mmol)at room temperature. The reaction mixture was stirred at 60° C. for 3 h.The reaction mixture was cooled to room temperature, quenched with coldwater (80 mL), extracted with DCM (3×50 mL), combined organic layerswere dried over Na₂SO₄ and concentrated to get crude compound. The crudecompound was purified by silica gel column chromatography, the compoundwas eluted in 0 to 30% EA in hexane, the fractions were collected andconcentrated to afford 4-bromo-5-chloro-1H-pyrrolo[2,3-c]pyridine (2.6g, 11.23 mmol, 82% yield) as light brown solid. LCMS retention time1.992 min [D]. MS m/z: 233.0 [M+2H]⁺.

Intermediate 1E: 5-chloro-4-methyl-1H-pyrrolo[2,3-c]pyridine

To a solution of 4-bromo-5-chloro-1H-pyrrolo[2,3-c]pyridine (2.6 g,11.23 mmol) and methylboronic acid (2.017 g, 33.7 mmol) in mixture ofTHF (2 mL) and water (0.2 mL) was added potassium phosphate tribasic(7.15 g, 33.7 mmol). The reaction mixture was purged with nitrogen for 5mins, then PdCl₂(dppf)-CH₂Cl₂ adduct (0.917 g, 1.123 mmol) was added.The reaction mixture was purged again for 2 mins. The reaction mixturewas heated in a sealed tube at 75° C. for 8 h. The reaction mixture wasdiluted with EtOAc (50 mL), washed with water (30 mL), brine (10 mL),dried (Na₂SO₄) and concentrated to get crude material. The crudematerial was purified by silica gel chromatography on an ISCO instrumentusing 24 g silica column, the compound was eluted in 30% EtOAc inhexanes, the fractions were collected and concentrated to afford5-chloro-4-methyl-1H-pyrrolo[2,3-c]pyridine (1.35 g, 8.10 mmol, 72.1%yield). LCMS retention time 1.623 min [D]. MS m/z: 167.1 [M+H]⁺.

Intermediate 1F: tert-butyl4-(4-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)-3,6-dihydro pyridine-1(2H)-carboxylate

A solution of 5-chloro-4-methyl-1H-pyrrolo[2,3-c]pyridine (1.35 g, 8.10mmol), tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate(2.76 g, 8.91 mmol) and potassium phosphate tribasic (5.16 g, 24.31mmol) in mixture of THF (20 mL) and water (2 mL) was degassed for 10 minwith nitrogen gas. Next, PdCl₂(dppf)-CH₂Cl₂ adduct (0.638 g, 0.810 mmol)was added and the reaction mixture was stirred at 80° C. for 16 h. Thereaction mixture was diluted with EtOAc (50 mL), washed with water (30mL), brine (10 mL), dried (Na₂SO₄) and concentrated to get crudematerial. The crude material was purified by silica gel chromatographyon an ISCO instrument using 24 g silica column, the compound was elutedin 30% EtOAc in hexanes, the fractions were collected and concentratedto afford tert-butyl4-(4-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)-5,6-dihydropyridine-1(2H)-carboxylate(2.05 g, 6.54 mmol, 81% yield) as an off-white solid. LCMS retentiontime 2.077 min [D]. MS m/z: 314.2 [M+H]⁺.

Intermediate 1G: tert-butyl4-(4-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)piperidine-1-carboxylate

To a solution of tert-butyl4-(4-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)-5,6-dihydropyridine-1(2H)-carboxylate(2.0 g, 6.38 mmol) in MeOH (20 mL) was added Pd/C (0.204 g, 1.915 mmol).The reaction mixture was stirred under hydrogen bladder at roomtemperature for 16 h. The reaction mass was filtered through celite,washed with MeOH, the filtrates were collected and concentrated toafford tert-butyl4-(4-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)piperidine-1-carboxylate (1.9g, 6.02 mmol, 94% yield) as a white solid. LCMS retention time 2.069 min[D]. MS m/z: 316.2 [M+H]⁺.

Intermediate 1H: tert-butyl4-(3-bromo-4-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)piperidine-1-carboxylate

To a solution of tert-butyl4-(4-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)piperidine-1-carboxylate (1.8g, 5.71 mmol) in DMF (20 mL) at 0° C. was added a solution of NBS (1.016g, 5.71 mmol) in DMF (3 mL). The reaction mixture was stirred at roomtemperature for 3 h. The reaction mass was concentrated, partitionedbetween EtOAc and water, the two layers were separated, the organiclayer was washed with water, brine solution, dried over Na₂SO₄ andconcentrated to afford tert-butyl4-(3-bromo-4-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)piperidine-1-carboxylate(1.8 g, 3.70 mmol, 65% yield) as light brown solid. LCMS retention time3.077 min [D]. MS m/z: 396.2 [M+2H]⁺.

Intermediate 11: tert-butyl3-bromo-5-(1-(tert-butoxycarbonyl)piperidin-4-yl)-4-methyl-1H-pyrrolo[2,3-c]pyridine-1-carboxylate

To a solution of tert-butyl4-(3-bromo-4-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)piperidine-1-carboxylate (1.8 g, 4.56 mmol) in THF (40 mL) at 0° C. wereadded TEA (1.273 mL, 9.13 mmol), Boc₂O (1.590 mL, 6.85 mmol) and DMAP(0.279 g, 2.282 mmol). The reaction mixture was stirred at roomtemperature for 6 h. The reaction mass was diluted with EtOAc (50 mL),the organic layer was washed with water and brine solution, dried overNa₂SO₄ and concentrated to get crude compound. The crude compound waspurified by silica gel column chromatography, the compound was eluted in20% EA in hexane, the fractions were collected and concentrated toafford tert-butyl3-bromo-5-(1-(tert-butoxycarbonyl)piperidin-4-yl)-4-methyl-1H-pyrrolo[2,3-c]pyridine-1-carboxylate(1.5 g, 3.03 mmol, 66% yield) as an off-white solid. LCMS retention time2.246 min [D]. MS m/z: 496.2 [M+2H]⁺.

Intermediate 1J: tert-butyl5-(1-(tert-butoxycarbonyl)piperidin-4-yl)-4-methyl-3-(prop-1-en-2-yl)-1H-pyrrolo[2,3-c]pyridine-1-carboxylate

A solution of tert-butyl3-bromo-5-(1-(tert-butoxycarbonyl)piperidin-4-yl)-4-methyl-1H-pyrrolo[2,3-c]pyridine-1-carboxylate(1.4 g, 2.83 mmol),4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (0.571 g,3.40 mmol) and potassium phosphate tribasic (1.803 g, 8.49 mmol) in THF(20 mL) and water (2 mL) solvent mixture was degassed for 10 min withnitrogen. Next, 2nd generation XPhos precatalyst (0.223 g, 0.283 mmol)was added and the reaction mixture was stirred at 80° C. for 16 h. Thereaction mixture was diluted with EtOAc (50 mL), washed with water (30mL), brine (10 mL), dried (Na₂SO₄) and concentrated to get crudematerial. The crude material was purified by silica gel chromatographyon an ISCO instrument using 24 g silica column, the compound was elutedin 25% EtOAc in hexanes, the fractions were collected and concentratedto afford tert-butyl5-(1-(tert-butoxycarbonyl)piperidin-4-yl)-4-methyl-3-(prop-1-en-2-yl)-1H-pyrrolo[2,3-c]pyridine-1-carboxylate(1.05 g, 2.305 mmol, 81% yield) as an off-white solid. LCMS retentiontime 0.81 min [D] MS m/z: 456.2 [M+H]⁺.

Intermediate 1K: tert-butyl5-(1-(tert-butoxycarbonyl)piperidin-4-yl)-3-isopropyl-4-methyl-1H-pyrrolo[2,3-c]pyridine-1-carboxylate

To a solution of tert-butyl5-(1-(tert-butoxycarbonyl)piperidin-4-yl)-4-methyl-3-(prop-1-en-2-yl)-1H-pyrrolo[2,3-c]pyridine-1-carboxylate(1.05 g, 2.305 mmol) in ethyl acetate (30 mL) was added Pd/C (0.123 g,1.152 mmol). The reaction mixture was stirred under hydrogen bladder for2 h. The reaction mass was filtered through celite, washed with MeOH,the filtrate was collected and concentrated to get crude compound. Thecrude was purified by silica gel column chromatography, the compound waseluted in 10% EA in hexane, the fractions were collected andconcentrated to afford tert-butyl5-(1-(tert-butoxycarbonyl)piperidin-4-yl)-3-isopropyl-4-methyl-1H-pyrrolo[2,3-c]pyridine-1-carboxylate(0.65 g, 1.419 mmol, 61.6% yield) as a gummy solid. LCMS retention time4.761 min [D]. MS m/z: 458.2 [M+H]⁺.

Intermediate 1L: tert-butyl5-(1-(tert-butoxycarbonyl)piperidin-4-yl)-3-isopropyl-4-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-c]pyridine-1-carboxylate

To a solution of tert-butyl5-(1-(tert-butoxycarbonyl)piperidin-4-yl)-3-isopropyl-4-methyl-1H-pyrrolo[2,3-c]pyridine-1-carboxylate(0.5 g, 1.093 mmol) in THF (12 mL) was added LDA (2.185 mL, 4.37 mmol)at −78° C. The reaction mixture was stirred at the same temperature for1.5 h, then 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.892mL, 4.37 mmol) was added. The reaction mixture was stirred for 1 h at−50° C. The reaction was quenched with aqueous NH₄Cl. The reactionmixture was extracted with EtOAc, washed with water, brine, dried overNa₂SO₄ and concentrated to get crude compound. The crude was purified bysilica gel column chromatography, the compound was eluted in 40% EA inhexane, the fractions were collected and concentrated to affordtert-butyl5-(1-(tert-butoxycarbonyl)piperidin-4-yl)-3-isopropyl-4-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-c]pyridine-1-carboxylate(0.4 g, 0.685 mmol, 62.7% yield) as a semi solid. LCMS retention time1.48 min [G]. MS m/z: 584.5 [M+H]⁺.

Intermediate 1M: tert-butyl5-(1-(tert-butoxycarbonyl)piperidin-4-yl)-3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-methyl-1H-pyrrolo[2,3-c]pyridine-1-carboxylate

A solution of tert-butyl5-(1-(tert-butoxycarbonyl)piperidin-4-yl)-3-isopropyl-4-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-c]pyridine-1-carboxylate(0.4 g, 0.685 mmol), 6-bromo-8-methoxy-[1,2,4]triazolo[1,5-a]pyridine(0.172 g, 0.754 mmol) and potassium phosphate tribasic (0.436 g, 2.056mmol) in 1,4-dioxane (8 mL) and water (1 mL) solvent mixture wasdegassed for 10 min with nitrogen. Next, PdCl₂(dppf)-CH₂Cl₂ adduct(0.056 g, 0.069 mmol) was added and the reaction mixture was stirred at90° C. for 8 h. The reaction mixture was diluted with EtOAc (50 mL),washed with water (30 mL), brine (10 mL), dried (Na₂SO₄) andconcentrated to get crude material. The crude material was purified bysilica gel chromatography on an ISCO instrument using 24 g silicacolumn, compound was eluted in 60% EtOAc in hexanes, the fractions werecollected and concentrated to afford tert-butyl5-(1-(tert-butoxycarbonyl)piperidin-4-yl)-3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-methyl-1H-pyrrolo[2,3-c]pyridine-1-carboxylate(0.3 g, 0.496 mmol, 72% yield) as an off-white solid. LCMS retentiontime 2.779 min [D]. MS m/z: 605.4 [M+H]⁺.

Example 1

To a stirred solution of tert-butyl5-(1-(tert-butoxycarbonyl)piperidin-4-yl)-3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-methyl-1H-pyrrolo[2,3-c]pyridine-1-carboxylate(0.3 g, 0.496 mmol) in DCM (1 mL) was added 4 M HCl in dioxane (1.240mL, 4.96 mmol) at 0° C. The reaction mixture was stirred at roomtemperature for 2 h and then concentrated to get crude compound. Thecrude compound was purified by preparative LCMS using method D2,fractions containing the product were combined and dried using Genevaccentrifugal evaporator to afford6-(3-isopropyl-4-methyl-5-(piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl)-8-methoxy-[1,2,4]triazolo[1,5-a] pyridine (0.18 g, 0.445 mmol, 90% yield). LCMS retention time1.356 min [P]. MS m/z: 405.1 [M+H]+; ¹H NMR (400 MHz, DMSO-d₆) δ ppm11.58 (br. s., 1H) 8.69 (d, J=1.22 Hz, 1H) 8.45-8.58 (m, 2H) 7.14 (d,J=0.98 Hz, 1H) 4.04 (s, 3H) 3.58-3.68 (m, 1H) 3.10-3.20 (m, 2H) 2.79 (t,J=11.74 Hz, 1H) 2.68 (s, 3H) 1.87-1.98 (m, 2H) 1.82 (s, 3H) 1.65 (d,J=11.49 Hz, 2H) 1.21-1.35 (m, 6H).

Example 22-(4-(3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)piperidin-1-yl)-N-methylacetamide

To a solution of6-(3-isopropyl-4-methyl-5-(piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl)-8-methoxy-[1,2,4]triazolo[1,5-a]pyridine(20 mg, 0.049 mmol) and 2-chloro-N-methylacetamide (7.98 mg, 0.074 mmol)in DMF (0.5 mL) and THF (1 mL) solvent mixture was added TEA (0.021 mL,0.148 mmol) at room temperature. The reaction mixture was stirred for 16h. The reaction mass was concentrated to get crude compound. The crudecompound was purified by preparative LCMS using method D2, fractionscontaining the product were combined and dried using Genevac centrifugalevaporator to afford2-(4-(3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)piperidin-1-yl)-N-methylacetamide(9.1 mg, 0.018 mmol, 36.8% yield). LCMS retention time 1.632 min [P]. MSm/z: 476.1 [M+H]+; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.52 (s, 1H) 8.69(d, J=1.22 Hz, 1H) 8.54 (s, 1H) 8.50 (s, 1H) 7.69 (d, J=3.67 Hz, 1H)7.14 (s, 1H) 4.04 (s, 3H) 3.57-3.66 (m, 1H) 3.17 (d, J=4.16 Hz, 1H)2.87-2.94 (m, 3H) 2.63-2.69 (m, 4H) 2.18-2.27 (m, 2H) 2.02-2.14 (m, 2H)1.91 (s, 3H) 1.62 (d, J=11.98 Hz, 2H) 1.28 (d, J=7.09 Hz, 6H).

Example 36-(4-fluoro-3-isopropyl-5-(piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl)-8-methoxy-[1,2,4]triazolo[1,5-a]pyridine

Intermediate 3A: 3-fluoro-4-methyl-5-nitropyridin-2(1H)-one

To a solution of 4-methyl-5-nitropyridin-2(1H)-one (30 g, 195 mmol) in amixture of acetonitrile (300 mL) and water (30 mL) was added Selectfluor(76 g, 214 mmol) at room temperature. The reaction mixture was stirredat 65° C. for 48 h. The reaction mass was partitioned between water andEtOAc, the organic layer was washed with water and brine, dried overNa₂SO₄ and concentrated to afford3-fluoro-4-methyl-5-nitropyridin-2(1H)-one (32.1 g, 121 mmol, 62% yield)as a gummy solid. LCMS retention time 2.075 min [D]. MS m/z: 171.0[M−H]⁺.

Intermediate 3B: 2-chloro-3-fluoro-4-methyl-5-nitropyridine

2-chloro-3-fluoro-4-methyl-5-nitropyridine (8 g, 42.0 mmol, 70% yield)was prepared according to the general procedure described inIntermediate 1B using 3-fluoro-4-methyl-5-nitropyridin-2-ol (19.1, 59.9mmol) as the starting intermediate. LCMS retention time 2.399 min [D].MS m/z: 189.1 [M−H]⁺.

Intermediate 3C:(E)-2-(2-chloro-3-fluoro-5-nitropyridin-4-yl)-N,N-dimethylethene-1-amine

(E)-2-(2-chloro-3-fluoro-5-nitropyridin-4-yl)-N,N-dimethylethenamine(6.5 g, 26.5 mmol, 70.0% yield) was prepared according to the generalprocedure described in Intermediate 1C using2-chloro-3-fluoro-4-methyl-5-nitropyridine (7.2 g, 37.8 mmol) as thestarting intermediate. LCMS retention time 2.634 min [D]. MS m/z: 246.0[M+H]⁺.

Intermediate 3D: 5-chloro-4-fluoro-1H-pyrrolo[2,3-c]pyridine

5-chloro-4-fluoro-1H-pyrrolo[2,3-c]pyridine (4.8 g, 28.1 mmol, 93%yield) was prepared according to the general procedure described inIntermediate 1D using(E)-2-(2-chloro-3-fluoro-5-nitropyridin-4-yl)-N,N-dimethylethenamine(7.4 g, 30.1 mmol) as the starting intermediate. LCMS retention time1.658 min [D]. MS m/z: 171.0 [M+H]⁺.

Intermediate 3E: tert-butyl4-(4-fluoro-1H-pyrrolo[2,3-c]pyridin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate

tert-butyl4-(4-fluoro-1H-pyrrolo[2,3-c]pyridin-5-yl)-5,6-dihydropyridine-1(2H)-carboxylate(6.1 g, 19.22 mmol, 72.9% yield) was prepared according to the generalprocedure described in Intermediate 1F using5-chloro-4-fluoro-1H-pyrrolo[2,3-c]pyridine (4.5 g, 26.4 mmol) as thestarting intermediate. LCMS retention time 2.582 min [D]. MS m/z: 318.2[M+H]⁺.

Intermediate 3F: tert-butyl4-(4-fluoro-1H-pyrrolo[2,3-c]pyridin-5-yl)piperidine-1-carboxylate

tert-butyl4-(4-fluoro-1H-pyrrolo[2,3-c]pyridin-5-yl)piperidine-1-carboxylate (5.75g, 18.00 mmol, 94% yield) was prepared according to the generalprocedure described in Intermediate 1G using tert-butyl4-(4-fluoro-1H-pyrrolo[2,3-c]pyridin-5-yl)-5,6-dihydropyridine-1(2H)-carboxylate(6.1 g, 19.22 mmol) as the starting intermediate. LCMS retention time2.647 min [D]. MS m/z: 320.2 [M+H]⁺.

Intermediate 3G: tert-butyl4-(3-bromo-4-fluoro-1H-pyrrolo[2,3-c]pyridin-5-yl)piperidine-1-carboxylate

tert-butyl4-(3-bromo-4-fluoro-1H-pyrrolo[2,3-c]pyridin-5-yl)piperidine-1-carboxylate(7.1 g, 17.83 mmol, 99% yield) was prepared according to the generalprocedure described in Intermediate 1H using tert-butyl4-(4-fluoro-1H-pyrrolo[2,3-c]pyridin-5-yl)piperidine-1-carboxylate (5.75g, 18.00 mmol) as the starting intermediate. LCMS retention time 3.067min [D]. MS m/z: 400.2 [M+2H]⁺.

Intermediate 3H: tert-butyl3-bromo-5-(1-(tert-butoxycarbonyl)piperidin-4-yl)-4-fluoro-1H-pyrrolo[2,3-c]pyridine-1-carboxylate

tert-butyl3-bromo-5-(1-(tert-butoxycarbonyl)piperidin-4-yl)-4-fluoro-1H-pyrrolo[2,3-c]pyridine-1-carboxylate(6.7 g, 13.44 mmol, 75% yield) was prepared according to the generalprocedure described in Intermediate 1I using tert-butyl4-(3-bromo-4-fluoro-1H-pyrrolo[2,3-c]pyridin-5-yl)piperidine-1-carboxylate(7.1 g, 17.83 mmol) as the starting intermediate. LCMS retention time1.894 min [D]. MS m/z: 500.0 [M+2H]⁺.

Intermediate 31: tert-butyl5-(1-(tert-butoxycarbonyl)piperidin-4-yl)-4-fluoro-3-(prop-1-en-2-yl)-1H-pyrrolo[2,3-c]pyridine-1-carboxylate

tert-butyl5-(1-(tert-butoxycarbonyl)piperidin-4-yl)-4-fluoro-3-(prop-1-en-2-yl)-1H-pyrrolo[2,3-c]pyridine-1-carboxylate(5.7 g, 12.40 mmol, 92% yield) was prepared according to the generalprocedure described in Intermediate 1J using tert-butyl3-bromo-5-(1-(tert-butoxycarbonyl)piperidin-4-yl)-4-fluoro-1H-pyrrolo[2,3-c]pyridine-1-carboxylate(6.7 g, 13.44 mmol) as the starting intermediate. LCMS retention time4.576 min [D]. MS m/z: 460.2 [M+H]⁺.

Intermediate 3J: tert-butyl5-(1-(tert-butoxycarbonyl)piperidin-4-yl)-4-fluoro-3-isopropyl-1H-pyrrolo[2,3-c]pyridine-1-carboxylate

tert-butyl5-(1-(tert-butoxycarbonyl)piperidin-4-yl)-4-fluoro-3-isopropyl-1H-pyrrolo[2,3-c]pyridine-1-carboxylate(4.6 g, 9.97 mmol, 80% yield) was prepared according to the generalprocedure described in Intermediate 1K using tert-butyl5-(1-(tert-butoxycarbonyl)piperidin-4-yl)-4-fluoro-3-(prop-1-en-2-yl)-1H-pyrrolo[2,3-c]pyridine-1-carboxylate(5.7 g, 12.40 mmol) as the starting intermediate. LCMS retention time1.602 min [D]. MS m/z: 462.2 [M+H]⁺.

Intermediate 3K: tert-butyl5-(1-(tert-butoxycarbonyl)piperidin-4-yl)-4-fluoro-3-isopropyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-c]pyridine-1-carboxylate

tert-butyl5-(1-(tert-butoxycarbonyl)piperidin-4-yl)-4-fluoro-3-isopropyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-c]pyridine-1-carboxylate(2.42 g, 3.87 mmol, 74.5% yield) was prepared according to the generalprocedure described in Intermediate 1L using tert-butyl5-(1-(tert-butoxycarbonyl)piperidin-4-yl)-4-fluoro-3-isopropyl-1H-pyrrolo[2,3-c]pyridine-1-carboxylate(2.4 g, 5.20 mmol) as the starting intermediate. LCMS retention time2.358 min [D]. MS m/z: 588.2 [M+H]⁺.

Intermediate 3L: tert-butyl5-(1-(tert-butoxycarbonyl)piperidin-4-yl)-4-fluoro-3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-pyrrolo[2,3-c]pyridine-1-carboxylate

tert-butyl5-(1-(tert-butoxycarbonyl)piperidin-4-yl)-4-fluoro-3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-pyrrolo[2,3-c]pyridine-1-carboxylate(0.42 g, 0.661 mmol, 48.5% yield) was prepared according to the generalprocedure described in Intermediate 1M using tert-butyl5-(1-(tert-butoxycarbonyl)piperidin-4-yl)-4-fluoro-3-isopropyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-c]pyridine-1-carboxylate(0.8 g, 1.362 mmol) as the starting intermediate. LCMS retention time3.396 min [D]. MS m/z: 609.3 [M+H]⁺.

Example 3

6-(4-fluoro-3-isopropyl-5-(piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl)-8-methoxy-[1,2,4]triazolo[1,5-a]pyridine (0.26 g, 0.637 mmol, 92% yield) was preparedaccording to the general procedure described in Example 1 usingtert-butyl5-(1-(tert-butoxycarbonyl)piperidin-4-yl)-4-fluoro-3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-pyrrolo[2,3-c]pyridine-1-carboxylate(0.42 g, 0.690 mmol) as the starting intermediate. LCMS retention time1.086 min [P]. MS m/z: 409.3 [M+H]+; ¹H NMR (400 MHz, DMSO-d₆) δ ppm12.01 (bs, 1H) 8.69 (d, J=1.0 Hz, 1H), 8.56 (d, J=2.4 Hz, 1H), 8.55 (s,1H), 7.17 (s, 1H), 4.07 (s, 3H), 3.19-3.09 (m, 3H), 2.78 (t, J=11.2 Hz,2H), 1.92 (d, J=8.8 Hz, 2H), 1.86 (s, 3H), 1.72 (d, J=12.7 Hz, 2H), 1.35(d, J=6.8 Hz, 6H).

Example 46-(3-isopropyl-5-(piperidin-4-yl)-1h-pyrrolo[2,3-c]pyridin-2-yl)-8-methyl-[1,2,4]triazolo[1,5-a]pyridine

Intermediate 4A: tert-butyl4-(1H-pyrrolo[2,3-c]pyridin-5-yl)-5,6-dihydropyridine-1(2H)-94carboxylate

To a solution of 5-bromo-1H-pyrrolo[2,3-c]pyridine (3.2 g, 16.24 mmol)in dioxane (60 mL) and water (20.00 mL) solvent mixture were addedtert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate(5.02 g, 16.24 mmol) and potassium phosphate tribasic (10.34 g, 48.7mmol). The reaction mixture was degassed with nitrogen for 5 min.,PdCl₂(dppf)-CH₂Cl2 adduct (1.326 g, 1.624 mmol) was added, and thereaction mixture was stirred in a sealed tube at 90° C. for 3 h. Thereaction mass was concentrated, then the residue was diluted with EtOAc(20 mL), the solids were filtered, the filtrate was collected andconcentrated to get crude compound. The crude compound was purified bysilica gel chromatography on an ISCO instrument using 40 g silicacolumn, the compound was eluted in 15% EA in hexanes, the fractions werecollected and concentrated to afford tert-butyl4-(1H-pyrrolo[2,3-c]pyridin-5-yl)-5,6-dihydropyridine-1(2H)-carboxylate(2.5 g, 8.35 mmol, 51% yield) as a pale brown solid. LCMS retention time0.95 min [L] MS m/z: 300.2 [M+H]⁺.

Intermediate 4B: tert-butyl4-(1H-pyrrolo[2,3-c]pyridin-5-yl)piperidine-1-carboxylate

To a solution of tert-butyl4-(1H-pyrrolo[2,3-c]pyridin-5-yl)-5,6-dihydropyridine-1(2H)-carboxylate(3.2 g, 10.69 mmol) in MeOH (20 mL) and EtOAc (20 mL) solvent mixturewas added Pd/C (1.138 g, 10.69 mmol). The reaction mixture was stirredat room temperature for 3 h under hydrogen. The reaction mass wasfiltered through celite, washed with EtOAc (2×50 mL) and concentrated toafford tert-butyl4-(1H-pyrrolo[2,3-c]pyridin-5-yl)piperidine-1-carboxylate (2.5 g, 8.30mmol, 78% yield) as an off-white solid. LCMS retention time 0.88 min [D]MS m/z: 302.2 [M+H]⁺.

Intermediate 4C: tert-butyl4-(3-bromo-1H-pyrrolo[2,3-c]pyridin-5-yl)piperidine-1-carboxylate

To a solution of tert-butyl4-(1H-pyrrolo[2,3-c]pyridin-5-yl)piperidine-1-carboxylate (300 mg, 0.995mmol) in DMF (5 mL) was added NBS (142 mg, 0.796 mmol) at 0° C. Thereaction mixture was stirred at same temperature for 1 h. The reactionwas quenched with ice (50 g). The reaction mixture was extracted withEtOAc (3×50 mL), the combined organic layer was concentrated to getcrude compound. The crude was purified by silica gel chromatography onan ISCO instrument using 24 g silica column, the compound was eluted in10% EA in hexanes, the fractions were collected and concentrated toafford tert-butyl 4-(3-bromo-1H-pyrrolo[2,3-c]pyridin-5-yl)piperidine-1-carboxylate (300 mg, 0.789 mmol, 79% yield) as an off-whitesolid. LCMS retention time 1.31 min [G] MS m/z: 382.1 [M+2H]⁺.

Intermediate 4D: tert-butyl4-(3-(prop-1-en-2-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)piperidine-1-carboxylate

tert-butyl 3-(3-isopropyl-1H-indol-5-yl)azetidine-1-carboxylate (700 mg,1.759 mmol, 33.4% yield) was prepared according to the general proceduredescribed in Intermediate 4A using tert-butyl4-(3-bromo-1H-pyrrolo[2,3-c]pyridin-5-yl)piperidine-1-carboxylate (2.5g, 6.57 mmol) as the starting intermediate. LCMS retention time 0.51 min[D] MS m/z: 340.8 [M+H]⁺.

Intermediate 4E:tert-butyl4-(3-isopropyl-1H-pyrrolo[2,3-c]pyridin-5-yl)piperidine-1-carboxylate

tert-butyl4-(3-isopropyl-1H-pyrrolo[2,3-c]pyridin-5-yl)piperidine-1-carboxylate(1.8 g, 2.52 mmol, 48% yield) was prepared according to the generalprocedure described in Intermediate 4B using tert-butyl4-(3-(prop-1-en-2-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)piperidine-1-carboxylate (1.9 g, 5.56 mmol) as the startingintermediate. LCMS retention time 0.80 min [D]. MS m/z: 344.2 [M+H]⁺.

Intermediate 4F: tert-butyl5-(1-(tert-butoxycarbonyl)piperidin-4-yl)-3-isopropyl-1H-pyrrolo[2,3-c]pyridine-1-carboxylate

To a solution of tert-butyl4-(3-isopropyl-1H-pyrrolo[2,3-c]pyridin-5-yl) piperidine-1-carboxylate(1.9 g, 5.53 mmol) in DCM (10 mL) were added Boc₂O (1.670 mL, 7.19 mmol)and DMAP (10.14 g, 83 mmol) at room temperature. The reaction mixturewas stirred at same temperature for 12 h. The reaction mass wasconcentrated to get crude compound. The crude compound was purified bysilica gel chromatography on an ISCO instrument using 12 g silicacolumn, the compound was eluted in 35% EA in hexanes, the fractions werecollected and concentrated to afford tert-butyl5-(1-(tert-butoxycarbonyl)piperidin-4-yl)-3-isopropyl-1H-pyrrolo[2,3-c]pyridine-1-carboxylate(1.2 g, 2.71 mmol, 49% yield) as an off-white solid. LCMS retention time1.99 min [D] MS m/z: 444.4 [M+H]⁺.

Intermediate 4G: tert-butyl5-(1-(tert-butoxycarbonyl)piperidin-4-yl)-3-isopropyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-c]pyridine-1-carboxylate

To a solution of tert-butyl5-(1-(tert-butoxycarbonyl)piperidin-4-yl)-3-isopropyl-1H-pyrrolo[2,3-c]pyridine-1-carboxylate(550 mg, 1.240 mmol) in THF (3 mL) was added LDA (2.480 mL, 4.96 mmol)at −78° C. The reaction mixture was stirred at the same temperature for1.5 h. Next, 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.769mL, 3.72 mmol) was added and the reaction mixture was stirred at −45° C.for 2 h. The reaction was quenched with ammonia chloride (20 mL). Thereaction mixture was separated, the organic layers were concentrated toget crude compound. The crude compound was purified by silica gelchromatography on an ISCO instrument using 24 g silica column, thecompound was eluted in 25% EA in hexanes, the fractions were collectedand concentrated to afford tert-butyl5-(1-(tert-butoxycarbonyl)piperidin-4-yl)-3-isopropyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-c]pyridine-1-carboxylate(320 mg, 0.562 mmol, 45% yield). LCMS retention time 1.03 min [D]. MSm/z: 514.4 [M+H-tBu]⁺.

Intermediate 4H:tert-butyl5-(1-(tert-butoxycarbonyl)piperidin-4-yl)-3-isopropyl-2-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-pyrrolo[2,3-c]pyridine-1-carboxylate

To a solution of tert-butyl5-(1-(tert-butoxycarbonyl)piperidin-4-yl)-3-isopropyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-c]pyridine-1-carboxylate(300 mg, 0.527 mmol) in dioxane (18 mL) and water (6.00 mL) solventmixture were added 6-bromo-8-methyl-[1,2,4]triazolo[1,5-a]pyridine (335mg, 1.580 mmol) and potassium phosphate tribasic (335 mg, 1.580 mmol).The reaction mixture was degassed with nitrogen for 5 min, potassiumphosphate tribasic (335 mg, 1.580 mmol) was added, and the reactionmixture was stirred in a sealed tube at 90° C. for 3 h. The reactionmass was concentrated, the residue was dissolved in EtOAc (50 mL), thesolid was filtered and washed with EtOAc (2×30 mL), the combinedfiltrates were collected and concentrated to get crude compound. Thecrude compound was purified by silica gel chromatography on an ISCOinstrument using 24 g silica column, the compound was eluted in 35% EAin hexanes, the fractions were collected and concentrated to affordtert-butyl5-(1-(tert-butoxycarbonyl)piperidin-4-yl)-3-isopropyl-2-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-pyrrolo[2,3-c]pyridine-1-carboxylate(150 mg, 0.261 mmol, 49.5% yield) as an off-white solid. LCMS retentiontime 1.16 min [D] MS m/z: 575.3 [M+H]⁺.

Example 4

To a solution of tert-butyl5-(1-(tert-butoxycarbonyl)piperidin-4-yl)-3-isopropyl-2-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-pyrrolo[2,3-c]pyridine-1-carboxylate(31 mg, 0.054 mmol) in DCM (2 mL) was added 4 M HCl in dioxane (1 mL,4.00 mmol).

The mixture was stirred at room temperature for 3 h. The reaction masswas concentrated and the residue was triturated with diethyl ether (2×10mL), and dried under vacuum to afford6-(3-isopropyl-5-(piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl)-8-methyl-[1,2,4]triazolo[1,5-a]pyridine(2.1 mg, 5.61 μmol, 10% yield) as a white solid. LCMS retention time1.209 min [G], MS m/z: 375.2 [M+H]+; ¹H NMR (400 MHz, METHANOL-d₄) δ ppm8.85 (s, 1H), 8.69 (s, 1H), 8.52 (s, 1H), 7.70 (s, 2H), 3.44-3.61 (m,3H), 3.38 (br. s., 1H), 3.05-3.27 (m, 3H), 2.75 (s, 3H), 2.03-2.27 (m,4H), 1.94 (s, 3H), 1.53 (d, J=6.85 Hz, 5H).

Example 52-(dimethylamino)-1-(4-(3-isopropyl-2-(8-methyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)piperidin-1-yl)ethan-1-one

To a solution of6-(3-isopropyl-5-(piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl)-8-methyl-[1,2,4]triazolo[1,5-a]pyridine(25 mg, 0.067 mmol) in DMF (1 mL) were added triethylamine (0.028 mL,0.200 mmol), 2-(dimethylamino)acetic acid (13.77 mg, 0.134 mmol) andHATU (76 mg, 0.200 mmol) at 0° C. The reaction mixture was stirred atroom temperature for 3 h. The reaction mass was purified by preparativeLCMS method D2, the fractions containing the product were combined anddried using Genevac centrifugal evaporator to afford2-(dimethylamino)-1-(4-(3-isopropyl-2-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)piperidin-1-yl)ethanone (11 mg, 0.024 mmol, 35.9% yield) as a palesolid. LCMS retention time 1.346 min [E]. MS m/z: 460.3 [M+H]+; ¹H NMR(400 MHz, DMSO-d₆) δ ppm 11.62 (s, 1H), 8.90 (s, 1H), 8.65 (s, 1H), 8.55(s, 1H), 7.62 (s, 1H), 7.53 (s, 1H), 4.52-4.48 (m, 1H), 4.16-4.11 (m,1H), 3.26-3.12 (m, 3H), 3.04-2.96 (m, 2H), 2.67-2.64 (m, 1H), 2.63 (s3H), 2.25 (s, 6H), 1.90-1.85 (m 2H), 1.82-1.75 (m, 1H), 1.66-1.62 (m,1H), 1.41 (d, J=6.85 Hz, 6H).

Example 66-(4-chloro-3-isopropyl-5-(piperazin-1-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl)-8-methoxy-[1,2,4]triazolo[1,5-a]pyridine

Intermediate 6A: tert-butyl4-(4-methyl-5-nitropyridin-2-yl)piperazine-1-carboxylate

To a solution of 2-bromo-4-methyl-5-nitropyridine (10 g, 46.1 mmol) inacetonitrile (50 mL) were added tert-butyl piperazine-1-carboxylate(8.58 g, 46.1 mmol) and DIPEA (12.07 mL, 69.1 mmol) at room temperature.The reaction mixture was stirred at 60° C. for 4 h. The solids werefiltered, washed with acetonitrile (50 mL) and dried under vacuum toafford tert-butyl4-(4-methyl-5-nitropyridin-2-yl)piperazine-1-carboxylate (10 g, 19.85mmol, 43% yield) as a white solid. LCMS retention time 1.39 min [G]. MSm/z: 323.5 [M+H]⁺.

Intermediate 6B:tert-butyl(E)-4-(4-(2-(dimethylamino)vinyl)-5-nitropyridin-2-yl)piperazine-1-carboxylate

To a solution tert-butyl4-(4-methyl-5-nitropyridin-2-yl)piperazine-1-carboxylate (24 g, 74.5mmol) in DMF (70 mL) was added 1,1-dimethoxy-N,N-dimethylmethanamine(49.8 mL, 372 mmol). The reaction mixture was stirred at 90° C. for 24h. The reaction mass was concentrated, the residue was dissolved in DCM(250 mL), washed with water (2×50 mL), brine (20 mL), dried (Na₂SO₄) andconcentrated to afford (E)-tert-butyl4-(4-(2-(dimethylamino)vinyl)-5-nitropyridin-2-yl)piperazine-1-carboxylate(12 g, 20.03 mmol, 27% yield) as an oil. LCMS retention time 1.39 min[L] MS m/z: 378.5 [M+H]⁺.

Intermediate 6C:tert-butyl(E)-4-(4-(2-(dimethylamino)vinyl)-5-nitropyridin-2-yl)piperazine-1-carboxylate

To a solution tert-butyl (E)-tert-butyl4-(4-(2-(dimethylamino)vinyl)-5-nitropyridin-2-yl)piperazine-1-carboxylate(15 g, 39.7 mmol) in MeOH (150 mL) was added Pd/C (1.5 g, 14.10 mmol).The reaction mixture was stirred at 60 psi under hydrogen in anautoclave for 12 h. The Pd/C was filtered through celite, washed withEtOAc (2×50 mL), the filtrates were collected and concentrated to affordtert-butyl 4-(1H-pyrrolo[2,3-c]pyridin-5-yl)piperazine-1-carboxylate(6.5 g, 16.34 mmol, 41.1% yield) as an off-white solid. LCMS retentiontime 2.10 min [L] MS m/z: 303.2 [M+H]⁺.

Intermediate 6D: tert-butyl4-(3-bromo-1H-pyrrolo[2,3-c]pyridin-5-yl)piperazine-1-carboxylate

tert-butyl4-(3-bromo-1H-pyrrolo[2,3-c]pyridin-5-yl)piperazine-1-carboxylate (6.5g, 15.00 mmol, 76% yield) was prepared according to the generalprocedure described in Intermediate 4C using tert-butyl4-(1H-pyrrolo[2,3-c]pyridin-5-yl) piperazine-1-carboxylate (6 g, 19.84mmol) as the starting intermediate. LCMS retention time 0.98 min [G]. MSm/z: 382.9 [M+H]⁺.

Intermediate 6E: tert-butyl3-bromo-5-(4-(tert-butoxycarbonyl)piperazin-1-yl)-1H-pyrrolo[2,3-c]pyridine-1-carboxylate

To a solution of tert-butyl4-(3-bromo-1H-pyrrolo[2,3-c]pyridin-5-yl)piperazine-1-carboxylate (1.1g, 2.89 mmol) in THF (20 mL) were added triethylamine (1.206 mL, 8.66mmol), Boc₂O (0.804 mL, 3.46 mmol) and DMAP (7.05 mg, 0.058 mmol) atroom temperature. The reaction mixture was stirred at same temperaturefor 12 h. The reaction mass was concentrated to get the crude compound.The crude compound was purified by silica gel chromatography on an ISCOinstrument using 24 g silica column, the compound was eluted in 35% EAin hexanes, the fractions were collected and concentrated to affordtert-butyl3-bromo-5-(4-(tert-butoxycarbonyl)piperazin-1-yl)-1H-pyrrolo[2,3-c]pyridine-1-carboxylate(900 mg, 1.458 mmol, 50% yield) as a gummy solid. LCMS retention time1.88 min [G] MS m/z: 483.3 [M+H]⁺.

Intermediate 6F: tert-butyl5-(4-(tert-butoxycarbonyl)piperazin-1-yl)-3-(prop-1-en-2-yl)-1H-pyrrolo[2,3-c]pyridine-1-carboxylate

tert-butyl5-(4-(tert-butoxycarbonyl)piperazin-1-yl)-3-(prop-1-en-2-yl)-1H-pyrrolo[2,3-c]pyridine-1-carboxylate (450 mg, 0.590 mmol, 29% yield) was preparedaccording to the general procedure described in Intermediate 4D usingtert-butyl5-(4-(tert-butoxycarbonyl)piperazin-1-yl)-3-isopropyl-1H-pyrrolo[2,3-c]pyridine-1-carboxylate(900 mg, 2.024 mmol) as the starting intermediate. LCMS retention time1.88 min [L] MS m/z: 443.5 [M+H]⁺.

Intermediate 6G: tert-butyl5-(4-(tert-butoxycarbonyl)piperazin-1-yl)-3-isopropyl-1H-pyrrolo[2,3-c]pyridine-1-carboxylate

tert-butyl5-(4-(tert-butoxycarbonyl)piperazin-1-yl)-3-isopropyl-1H-pyrrolo[2,3-c]pyridine-1-carboxylate(310 mg, 0.572 mmol, 56% yield) was prepared according to the generalprocedure described in Intermediate 4E using tert-butyl5-(4-(tert-butoxycarbonyl)piperazin-1-yl)-3-(prop-1-en-2-yl)-1H-pyrrolo[2,3-c]pyridine-1-carboxylate(450 mg, 1.017 mmol) as the starting intermediate. LCMS retention time1.92 min [L] MS m/z: 445.5 [M+H]⁺.

Intermediate 6H:tert-butyl5-(4-(tert-butoxycarbonyl)piperazin-1-yl)-4-chloro-3-isopropyl-1H-pyrrolo[2,3-c]pyridine-1-carboxylate

To a solution of tert-butyl5-(4-(tert-butoxycarbonyl)piperazin-1-yl)-3-isopropyl-1H-pyrrolo[2,3-c]pyridine-1-carboxylate(1 g, 2.249 mmol) in DCE (10 mL) was added NCS (0.751 g, 5.62 mmol) atroom temperature. The reaction mixture was stirred at room temperaturefor 12 h. The reaction was quenched with water. The reaction mixture wasextracted with DCM, the organic layer was concentrated to get crudecompound. The crude compound was purified by silica gel chromatographyon an ISCO instrument using 24 g silica column, the compound was elutedin 20% EA in hexanes, the fractions were collected and concentrated toafford tert-butyl5-(4-(tert-butoxycarbonyl)piperazin-1-yl)-4-chloro-3-isopropyl-1H-pyrrolo[2,3-c]pyridine-1-carboxylate(150 mg, 0.307 mmol, 13% yield) as an off-white solid. LCMS retentiontime 3.487 min [G], MS m/z: 479.2 [M+H]⁺.

Intermediate 61: tert-butyl5-(4-(tert-butoxycarbonyl)piperazin-1-yl)-4-chloro-3-isopropyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-c]pyridine-1-carboxylate

tert-butyl5-(4-(tert-butoxycarbonyl)piperazin-1-yl)-4-chloro-3-isopropyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-c]pyridine-1-carboxylate(158 mg, 0.243 mmol, 68.4% yield) was prepared according to the generalprocedure described in Intermediate 1L using tert-butyl5-(4-(tert-butoxycarbonyl)piperazin-1-yl)-4-chloro-3-isopropyl-1H-pyrrolo[2,3-c]pyridine-1-carboxylate(170 mg, 0.355 mmol) as the starting intermediate. LCMS retention time3.328 min [G], MS m/z: 605.4 [M+H]⁺.

Intermediate 6J: tert-butyl5-(4-(tert-butoxycarbonyl)piperazin-1-yl)-4-chloro-3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-pyrrolo[2,3-c]pyridine-1-carboxylate

tert-butyl5-(4-(tert-butoxycarbonyl)piperazin-1-yl)-4-chloro-3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-pyrrolo[2,3-c]pyridine-1-carboxylate(180 mg, 0.207 mmol, 62.6% yield) was prepared according to the generalprocedure described in Intermediate 1M using tert-butyl5-(4-(tert-butoxycarbonyl)piperazin-1-yl)-4-chloro-3-isopropyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-c]pyridine-1-carboxylate(200 mg, 0.331 mmol) as the starting intermediate. LCMS retention time1.96 min [D], MS m/z: 628.2 [M+H]⁺.

Example 6

6-(4-chloro-3-isopropyl-5-(piperazin-1-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl)-8-methoxy-[1,2,4]triazolo[1,5-a]pyridine (140 mg, 0.329 mmol, 86% yield) was preparedaccording to the general procedure described in Example 4 usingtert-butyl5-(4-(tert-butoxycarbonyl)piperazin-1-yl)-4-chloro-3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-pyrrolo[2,3-c]pyridine-1-carboxylate(240 mg, 0.383 mmol) in HCl (3 mL, 12.00 mmol) as the startingintermediate. LCMS retention time 1.329 min [E], MS m/z: 426.2 [M+H]+;¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.71 (d, J=1.2 Hz, 1H), 8.54 (s, 1H),8.45 (s, 1H), 7.15 (s, 1H), 4.04 (s, 3H), 3.06 (d, J=5.1 Hz, 4H),2.99-2.91 (m, 4H), 1.87 (s, 2H), 1.33 (d, J=7.3 Hz, 6H).

Example 76-(3-isopropyl-5-(piperazin-1-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl)-8-methoxy-[1,2,4]triazolo[1,5-a]pyridine

Intermediate 7A:tert-butyl5-(4-(tert-butoxycarbonyl)piperazin-1-yl)-3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-pyrrolo[2,3-c]pyridine-1-carboxylate

To a solution of tert-butyl5-(4-(tert-butoxycarbonyl)piperazin-1-yl)-4-chloro-3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-pyrrolo[2,3-c]pyridine-1-carboxylate(100 mg, 0.160 mmol) in MeOH (5 mL) was added Pd/C (17.00 mg, 0.160mmol). The mixture was stirred at room temperature under hydrogenbladder for 3 h. The reaction mass was filtered, washed with EtOAc (2×50mL) and concentrated to afford tert-butyl5-(4-(tert-butoxycarbonyl)piperazin-1-yl)-3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-pyrrolo[2,3-c]pyridine-1-carboxylate(65 mg, 0.019 mmol, 11% yield) as a pale solid. LCMS retention time 1.64min [D] MS m/z: 592.6 [M+H]⁺.

Example 7

6-(3-isopropyl-5-(piperazin-1-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl)-8-methoxy-[1,2,4]triazolo[1,5-a]pyridine(0.7 mg, 1.788 μmol, 2% yield) was prepared according to the generalprocedure described in Example 4 using tert-butyl5-(4-(tert-butoxycarbonyl)piperazin-1-yl)-3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-pyrrolo[2,3-c]pyridine-1-carboxylate (65 mg,0.110 mmol) as the starting intermediate. LCMS retention time 1.18 min[F], MS m/z: 392.1 [M+H]+; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.30 (s,1H), 8.64 (s, 1H), 8.53 (s, 1H), 8.42 (s, 1H), 7.17 (s, 1H), 6.90 (s,1H), 4.07 (s, 3H), 2.90 (br. s., 4H), 1.90 (s, 2H), 1.42 (d, J=7.1 Hz,6H).

Example 421-(4-fluoro-3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)-N-(oxetan-3-yl)piperidin-4-amine

Intermediate 42A:8-(4-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)-1,4-dioxa-8-azaspiro[4.5]decane

8-(4-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)-1,4-dioxa-8-azaspiro[4.5]decane(3.7 g, 9.08 mmol, 68.3% yield) was prepared as described in thepreparation of Intermediate 213B using5-chloro-4-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridine (4.0 g, 13.30 mmol) and1,4-dioxa-8-azaspiro[4.5]decane (2.86 g, 19.94 mmol) as the startingintermediates. LCMS retention time 3.410 min [D]. MS (E⁻) m/z: 408.2(M+H).

Intermediate 42B:8-(3-bromo-4-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)-1,4-dioxa-8-azaspiro[4.5]decane

8-(3-bromo-4-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)-1,4-dioxa-8-azaspiro[4.5]decane(5.01 g, 10.30 mmol, 87% yield) was prepared as described in thepreparation of Intermediate 213C using8-(4-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)-1,4-dioxa-8-azaspiro[4.5]decane(4.8 g, 11.78 mmol) as the starting intermediate. LCMS retention time1.77 min [L]. MS (E⁻) m/z: 488.8 (M+2H).

Intermediate 42C:8-(4-fluoro-3-(prop-1-en-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)-1,4-dioxa-8-azaspiro[4.5]decane

8-(4-fluoro-3-(prop-1-en-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)-1,4-dioxa-8-azaspiro[4.5]decane(3.8 g, 8.49 mmol, 82% yield) was prepared as described in thepreparation of intermediate 213D using8-(3-bromo-4-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)-1,4-dioxa-8-azaspiro[4.5]decane(5.01 g, 10.30 mmol) and4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (2.077 g,12.36 mmol) as the starting intermediates. LCMS retention time 4.033 min[D]. MS (E⁻) m/z: 448.2 (M+H).

Intermediate 42D:8-(4-fluoro-3-isopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)-1,4-dioxa-8-azaspiro[4.5]decane

8-(4-fluoro-3-isopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)-1,4-dioxa-8-azaspiro[4.5]decane(3.6 g, 8.01 mmol, 97% yield) was prepared as described in thepreparation of Intermediate 213E using8-(4-fluoro-3-(prop-1-en-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)-1,4-dioxa-8-azaspiro[4.5]decane(3.7 g, 8.27 mmol) as the starting intermediate. LCMS retention time4.193 min [D]. MS (E⁻) m/z: 450.2 (M+H).

Intermediate 42E:8-(4-fluoro-3-isopropyl-1H-pyrrolo[2,3-c]pyridin-5-yl)-1,4-dioxa-8-azaspiro[4.5]decane

8-(4-fluoro-3-isopropyl-1H-pyrrolo[2,3-c]pyridin-5-yl)-1,4-dioxa-8-azaspiro[4.5]decane(1.4 g, 4.38 mmol, 79% yield) was prepared as described in thepreparation of Intermediate 213F using8-(4-fluoro-3-isopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)-1,4-dioxa-8-azaspiro[4.5]decane(2.5 g, 5.56 mmol) as the starting intermediate. LCMS retention time2.709 min [D]. MS (E⁻) m/z: 320.2 (M+H).

Intermediate 42F: tert-butyl4-fluoro-3-isopropyl-5-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)-1H-pyrrolo[2,3-c]pyridine-1-carboxylate

tert-butyl4-fluoro-3-isopropyl-5-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)-1H-pyrrolo[2,3-c]pyridine-1-carboxylate(1.41 g, 3.36 mmol, 89% yield) was prepared as described in thepreparation of Intermediate 213G using8-(4-fluoro-3-isopropyl-1H-pyrrolo[2,3-c]pyridin-5-yl)-1,4-dioxa-8-azaspiro[4.5]decane(1.2 g, 3.76 mmol) as the starting intermediate. LCMS retention time4.227 min [D]. MS (E⁻) m/z: 420.2 (M+H).

Intermediate 42G: tert-butyl4-fluoro-3-isopropyl-5-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-c]pyridine-1-carboxylate

tert-butyl4-fluoro-3-isopropyl-5-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-c]pyridine-1-carboxylate(1.26 g, 2.310 mmol, 69.2% yield) was prepared as described in thepreparation of Intermediate 213H using tert-butyl4-fluoro-3-isopropyl-5-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)-1H-pyrrolo[2,3-c]pyridine-1-carboxylate (1.4 g, 3.34 mmol) as the starting intermediate.LCMS retention time 4.527 min [D]. MS (E⁻) m/z: 546.3 (M+H).

Intermediate 42H: tert-butyl4-fluoro-3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)-1H-pyrrolo[2,3-c]pyridine-1-carboxylate

tert-butyl4-fluoro-3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)-1H-pyrrolo[2,3-c]pyridine-1-carboxylate(0.51 g, 0.900 mmol, 78% yield) was prepared as described in thepreparation of Intermediate 2131 using tert-butyl4-fluoro-3-isopropyl-5-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-c]pyridine-1-carboxylate(0.63 g, 1.155 mmol) and6-bromo-8-methoxy-[1,2,4]triazolo[1,5-a]pyridine (0.342 g, 1.501 mmol)as the starting intermediates. LCMS retention time 3.460 min [D]. MS(E⁻) m/z: 567.5 (M+H).

Intermediate 421:1-(4-fluoro-3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)piperidin-4-one

1-(4-fluoro-3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)piperidin-4-one(0.32 g, 0.757 mmol, 95% yield) was prepared as described in thepreparation of Example 4 using tert-butyl4-fluoro-3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)-1H-pyrrolo[2,3-c]pyridine-1-carboxylate(0.45 g, 0.794 mmol) as the starting intermediate. LCMS retention time2.129 min [D]. MS (E⁻) m/z: 423.2 (M+H).

Example 42

To a solution of1-(4-fluoro-3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)piperidin-4-one(25 mg, 0.059 mmol) and oxetan-3-amine (6.49 mg, 0.089 mmol) in mixtureof DMF (0.5 mL) and THF (0.5 mL) was added AcOH (0.339 μl, 5.92 μmol).The reaction mixture was stirred for 12 h at ambient temperature. Sodiumcyanoborohydride (7.44 mg, 0.118 mmol) was added, and the reactionmixture was stirred for 1 h at ambient temperature. The reaction wasquenched with 0.2 ml of water. The reaction mixture was concentrated toget crude compound. The crude material was purified by Preparative LCMSusing method D2, fractions containing the product was combined and driedusing Genevac centrifugal evaporator to afford1-(4-fluoro-3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)-N-(oxetan-3-yl)piperidin-4-amine(16.6 mg, 0.034 mmol, 57.0% yield). LCMS retention time 1.383 min [P].MS m/z: 480.3 [M+H]+; ¹H NMR (400 MHz, DMSO-d₆) δ 11.77 (s, 1H), 8.67(s, 1H), 8.54 (s, 1H), 8.29 (s, 1H), 7.15 (s, 1H), 4.66 (t, J=6.6 Hz,2H), 4.36 (t, J=6.2 Hz, 2H), 4.06 (s, 4H), 3.26 (br. s., 2H), 3.17 (s,1H), 2.80 (t, J=11.9 Hz, 2H), 1.91 (s, 2H), 1.79 (d, J=13.9 Hz, 2H),1.50-1.38 (m, 2H), 1.34 (d, J=7.1 Hz, 6H).

Example 213 6-(3-isopropyl-4-methyl-5-(piperazin-1-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl)-8-methoxy-[1,2,4]triazolo[1,5-a]pyridine

Intermediate (213A):5-chloro-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridine

To a solution of 5-chloro-4-methyl-1H-pyrrolo[2,3-c]pyridine (5.6 g,33.6 mmol) in dry THF (120 mL) was added sodium hydride (1.266 g, 52.8mmol) portion wise at 0° C., then stirred for 30 mins, then SEM-Cl (7.49mL, 42.2 mmol) was added to the reaction mixture at 0° C. The reactionwas continued for 4 hrs at ambient temperature. The reaction wasquenched with aqueous NH₄Cl solution. The mixture was partitionedbetween water and EtOAc. Combined organic layers were washed with water,brine solution, dried over Na₂SO₄ and concentrated, then purified oversilica gel eluting 40% EA/hexane to get5-chloro-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridine(8.9 g, 30.0 mmol, 89% yield). LCMS retention time 3.500 min [D]. MS(E⁻) m/z: 297.3 (M+H).

Intermediate 213B: tert-butyl4-(4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)piperazine-1-carboxylate

A solution of5-chloro-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridine(5 g, 16.84 mmol) and tert-butyl piperazine-1-carboxylate (3.76 g, 20.21mmol) in 1,4-Dioxane (60 mL) was purged with nitrogen for 5 mins, thenchloro(2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(0.680 g, 0.875 mmol) was added. The reaction mixture was again purgedfor 2 min and heated in a sealed tube at 110° C. for 3 h. The reactionmixture was filtered through Celite and was diluted with EtOAc (50 mL),washed with water (30 mL), brine (10 mL), dried (Na₂SO₄) andconcentrated to get crude material.

The crude material was purified by silica gel chromatography on an ISCOinstrument using 24 g silica column, the compound was eluted in 30%EtOAc in hexanes, the fractions were collected and concentrated toafford tert-butyl4-(4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)piperazine-1-carboxylate(5.1 g, 11.42 mmol, 67.8% yield). LCMS retention time 1.46 min [L]. MS(E⁻) m/z: 447.3 (M+H).

Intermediate 213C: tert-butyl4-(3-bromo-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)piperazine-1-carboxylate

To a solution of tert-butyl4-(4-methyl-1-((2-(trimethylsilyl)ethoxyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)piperazine-1-carboxylate(3.6 g, 8.06 mmol) in DMF (60 mL) at 0° C. was added a solution of NBS(1.41 g, 8.08 mmol) in DMF (20 mL). The reaction mixture was stirred for3 h at room temperature. The reaction mixture was concentrated undervacuum and 50 mL of water was added. The mixture was extracted withEtOAc(2×100 ml), combined organic layers washed with brine solution,dried over Na₂SO₄, concentrated and purified over silica gel eluting 25%EA in hexane to affordtert-butyl4-(3-bromo-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)piperazine-1-carboxylate(3.5 g, 6.66 mmol, 83% yield). LCMS retention time 1.73 min [L]. MS (E⁻)m/z: 527.3

Intermediate 213D: tert-butyl4-(4-methyl-3-(prop-1-en-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)piperazine-1-carboxylate

To a solution of4-(3-bromo-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)piperazine-1-carboxylate(3.4 g, 6.47 mmol) and4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (3.04 g,18.12 mmol) in mixture of THF (160 mL) and water (16 mL) was addedpotassium phosphate tribasic (4.12 g, 19.41 mmol). The reaction mixturewas purged with nitrogen for 5 mins, then 2nd generation XPhosprecatalyst (0.51 g, 0.647 mmol) was added. The reaction mixture waspurged again for 2 mins. The reaction mixture was heated in a sealedtube at 60° C. for 2 h. The reaction mass was cooled and filteredthrough small pad of Celite. The filtrate obtained was concentrated toprovide crude material. The crude material was purified by columnchromatography through silica gel eluting 25% EtOAc in hexane to affordtert-butyl4-(4-methyl-3-(prop-1-en-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)piperazine-1-carboxylate(2.6 g, 5.34 mmol, 83% yield). LCMS retention time 1.79 min [L]. MS (E⁻)m/z: 487.5 (M+H).

Intermediate 213E: tert-butyl4-(3-isopropyl-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)piperazine-1-carboxylate

To a solution of tert-butyl4-(4-methyl-3-(prop-1-en-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)piperazine-1-carboxylate(3.5 g, 7.19 mmol) was taken in ethyl acetate (120 mL). Pd—C(0.71 g,7.19 mmol) was added and the reaction mixture was stirred under H2pressure (bladder) for 2 h. The reaction mixture was filtered throughCelite, washed the Celite bed with MeOH, MeOH was concentrated undervacuum to get tert-butyl4-(3-isopropyl-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)piperazine-1-carboxylate(2.3 g, 4.71 mmol, 65.4% yield). LCMS retention time 1.83 min [L]. MS(E⁻) m/z: 489.4 (M+H).

Intermediate 213F: tert-butyl4-(3-isopropyl-4-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)piperazine-1-carboxylate

To a solution of tert-butyl4-(3-isopropyl-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)piperazine-1-carboxylate (2.6 g,5.32 mmol) in DMF (30 mL) at 0° C. was added TBAF (21.28 mL, 21.28 mmol)and ethylenediamine (1.602 mL, 23.94 mmol). The reaction mixture wasstirred for 6 h at 80° C. The reaction mixture was concentrated andpartitioned between water and EtOAc, the organic layer was separated andwashed with water, brine solution, dried over Na₂SO₄, concentrated toget tert-butyl4-(3-isopropyl-4-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)piperazine-1-carboxylate(1.81 g, 5.05 mmol, 95% yield). LCMS retention time 1.07 min [L]. MS(E−) m/z: 359.3 (M+H).

Intermediate 213G: tert-butyl5-(4-(tert-butoxycarbonyl)piperazin-1-yl)-3-isopropyl-4-methyl-1H-pyrrolo[2,3-c]pyridine-1-carboxylate

To a solution of tert-butyl5-(4-(tert-butoxycarbonyl)piperazin-1-yl)-3-isopropyl-4-methyl-1H-pyrrolo[2,3-c]pyridine-1-carboxylate(1.5 g, 3.27 mmol, 58.6% yield) was prepared as described in thepreparation of Intermediate 1I using tert-butyl4-(3-isopropyl-4-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)piperazine-1-carboxylate(2 g, 5.58 mmol) as the starting intermediate. LCMS retention time 1.96min [L]. MS (E⁻) m/z: 459.5 (M+H).

Intermediate 213H: tert-butyl5-(4-(tert-butoxycarbonyl)piperazin-1-yl)-3-isopropyl-4-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-c]pyridine-1-carboxylate

To a solution of tert-butyl5-(4-(tert-butoxycarbonyl)piperazin-1-yl)-3-isopropyl-4-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-c]pyridine-1-carboxylate(1.22 g, 2.087 mmol, 80% yield) was prepared as described in thepreparation of Intermediate 1L using tert-butyl5-(4-(tert-butoxycarbonyl)piperazin-1-yl)-3-isopropyl-4-methyl-1H-pyrrolo[2,3-c]pyridine-1-carboxylate(1.2 g, 2.62 mmol) and2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (5.34 mL, 26.2mmol) as the starting intermediates. LCMS retention time 3.155 min [D].MS (E⁻) m/z: 585.4 (M+H).

Intermediate 213I: tert-butyl5-(4-(tert-butoxycarbonyl)piperazin-1-yl)-3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-methyl-1H-pyrrolo[2,3-c]pyridine-1-carboxylate

To a solution of tert-butyl5-(4-(tert-butoxycarbonyl)piperazin-1-yl)-3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-methyl-1H-pyrrolo[2,3-c]pyridine-1-carboxylate(0.51 g, 0.842 mmol, 82% yield) was prepared as described in thepreparation of Intermediate 1M using tert-butyl5-(4-(tert-butoxycarbonyl)piperazin-1-yl)-3-isopropyl-4-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-c]pyridine-1-carboxylate(0.6 g, 1.026 mmol) and 6-bromo-8-methoxy-[1,2,4]triazolo[1,5-a]pyridine(0.281 g, 1.232 mmol) as the starting intermediates. LCMS retention time2.23 min [L]. MS (E⁻) m/z: 606.5 (M+H).

Example 213

6-(3-isopropyl-4-methyl-5-(piperazin-1-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl)-8-methoxy-[1,2,4]triazolo[1,5-a]pyridine(1.4 mg, 3.45 μmol, 10.46% yield) was prepared as described in thepreparation of Example 4 using tert-butyl 5-(4-(tert-butoxycarbonyl)piperazin-1-yl)-3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-methyl-1H-pyrrolo[2,3-c]pyridine-1-carboxylate(20 mg, 0.033 mmol) as the starting intermediate. LCMS retention time1.055 mi [D4]. MS (E⁻) m/z: 406.2 (M+H). ¹H NMR (400 MHz, DMSO-d₆) δ11.44 (s, 1H), 8.69 (d, J=1.5 Hz, 1H), 8.54 (s, 1H), 8.34 (s, 1H), 7.15(d, J=1.5 Hz, 1H), 4.04 (s, 3H), 3.62 (d, J=7.0 Hz, 1H), 2.92-2.86 (m,8H), 2.66 (s, 4H), 1.26 (d, J=7.0 Hz, 6H).

The examples in Table 1 were prepared according to the generalprocedures described in the above examples.

TABLE 1 Ret Ex. Mol. LCMS Time HPLC No. Structure Wt. M⁺ (min) Method  8

408.55 409.3 0.76 QC- ACN- TFA-XB  9

490.69 491.4 1.35 QC- ACN- AA-XB  10

479.56 480.3 1.2 P  11

461.57 462 1.591 P  12

475.6 476.1 1.476 P  13

406.51 407 0.897 Q  14

514.62 515.3 1.53 P  15

463.56 464.3 1.461 P  16

460.58 461.1 1.766 P  17

492.6 493.3 1.551 P  18

450.56 451.3 1.285 P  19

465.53 466.3 1.38 P  20

479.56 480.3 1.442 P  21

466.56 467.3 1.363 P  22

491.62 492.3 1.457 P  23

445.57 446.1 1.559 P  24

489.62 490.1 1.599 P  25

510.66 511 1.742 P  26

459.6 460.1 1.637 P  27

459.6 460.2 1.401 P  28

388.52 389.1 1.323 P  29

491.62 492.3 1.369 P  30

444.58 445.1 1.745 P  31

473.63 474.2 1.578 P  32

489.62 490.2 1.533 P  33

446.6 447.1 1.537 P  34

493.59 494.3 1.381 P  35

430.6 431.1 1.491 P  36

473.63 474.2 1.493 P  37

493.59 494.3 1.289 P  38

464.55 465.3 1.571 P  39

463.56 464.3 1.259 P  40

476.59 477.3 1.371 P  41

474.51 475.2 2.113 P  42

479.56 480.3 1.383 P  43

477.59 478.3 1.492 P  44

489.6 490.3 1.394 P  45

506.63 507.4 1.426 P  46

462.57 463.3 1.31 P  47

507.66 508.4 1.921 P  48

476.64 477.4 1.875 P  49

478.62 479.4 1.367 P  50

502.64 503.3 1.421 P  51

461.59 462 1.368 p  52

477.63 478 1.434 p  53

485.64 486.4 1.573 p  54

501.68 502.4 1.448 p  55

459.64 460.4 1.381 p  56

485.64 486.3 1.796 p  57

498.68 499 1.402 p  58

486.71 487.4 1.625 p  59

474.61 475.3 1.273 p  60

460.63 461 1.38 p  61

458.65 459.3 1.532 p  62

488.64 489.4 1.057 p  63

446.6 447.3 1.381 p  64

523.66 524.4 1.396 p  65

477.59 478.3 1.329 p  66

477.59 478.3 1.43 p  67

507.61 508.3 1.348 p  68

463.61 464.3 1.346 p  69

449.58 450.4 1.32 p  70

447.56 448.3 1.276 p  71

421.52 422.3 1.2 p  72

522.63 523.3 1.382 p  73

464.59 465.3 1.331 p  74

494.62 495.3 1.331 P  75

462.57 463.3 1.514 P  76

478.62 479.4 1.605 P  77

464.59 465.3 1.543 P  78

493.59 494 1.828 P  79

521.64 522 1.68 P  80

462.57 463.3 1.511 P  81

476.6 477.3 1.576 P  82

490.63 491.3 1.362 P  83

463.61 464 1.399 P  84

476.64 477.4 1.844 P  85

462.62 463 1.738 P  86

475.64 476 1.298 P  87

459.6 460 1.427 P  88

489.67 490 1.361 P  89

522.67 523.4 1.331 P  90

458.65 459.3 1.319 P  91

472.64 473.4 1.686 P  92

488.68 489.4 1.606 P  93

446.56 447.3 1.329 P  94

474.61 475 1.597 P  95

460.63 461.4 1.645 P  96

476.63 477.4 1.346 P  97

408.57 409.3 1.461 P  98

476.59 477 1.145 P  99

481.58 482.2 1.265 P 100

507.61 508.3 1.263 P 101

479.6 480.3 1.295 P 102

465.58 466.4 1.264 P 103

493.59 494.2 1.642 D 104

493.59 494.3 1.529 P 105

492.6 493.3 1.515 P 106

492.6 493.4 1.912 P 107

462.57 463.3 1.8 P 108

462.62 463.3 1.607 P 109

446.57 447.3 1.352 P 110

490.63 491.3 1.599 P 111

503.63 504.4 1.476 P 112

473.67 474 1.777 P 113

459.64 460 1.357 P 114

517.61 518 1.967 P 115

517.61 518.3 1.746 P 116

460.63 461.4 1.503 P 117

522.67 523.3 1.602 P 118

472.59 473.3 1.249 P 119

500.69 501.4 1.355 P 120

500.69 501 1.615 P 121

472.64 473.4 1.39 P 122

488.68 489.4 1.371 P 123

476.63 477 1.479 P 124

459.64 460 1.546 P 125

449.53 450.3 1.424 P 126

463.59 464 1.46 P 127

490.51 491.3 2.054 P 128

464.59 465.3 1.432 P 129

491.62 492.3 1.41 P 130

477.59 478.3 1.582 P 131

507.61 508 1.886 P 132

488.61 489.3 1.707 P 133

488.61 489.3 1.392 P 134

504.65 505.4 1.381 P 135

462.62 463.4 1.528 P 136

462.62 463 1.488 P 137

475.6 476.3 1.497 P 138

461.61 462.3 1.482 P 139

501.64 502.3 1.505 P 140

459.6 460 1.596 P 141

472.59 473.3 1.208 P 142

498.68 499.4 1.691 P 143

458.65 459.3 1.633 P 144

460.63 461.4 1.564 P 145

446.6 447.3 1.215 P 146

477.59 478 1.508 P 147

503.65 504.4 1.558 P 148

469.64 470.3 1.856 P 149

498.62 499.3 1.572 P 150

437.56 438.3 1.605 P 151

366.48 367.3 1.209 P 152

423.54 424 1.532 P 153

451.59 452.3 1.579 P 154

490.61 491 1.243 P 155

462.56 463 1.312 P 156

495.6 496.4 1.255 P 157

465.58 466.4 1.267 P 158

478.58 479.3 1.48 P 159

464.59 465.3 1.573 P 160

506.63 507.3 1.312 P 161

504.61 505.3 1.661 P 162

492.64 493.3 1.601 P 163

448.59 449.3 1.408 P 164

478.62 479.4 1.604 P 165

460.6 461.3 1.37 P 166

463.61 464 1.396 P 167

491.66 492 1.695 P 168

476.64 477.3 1.497 P 169

489.67 490.4 1.656 P 170

487.65 488.4 1.563 P 171

504.65 505 1.728 P 172

504.65 505.4 2.077 P 173

503.7 504 1.539 P 174

476.6 477.3 1.568 P 175

524.66 525.4 1.817 P 176

502.66 503.4 1.504 P 177

432.57 433 1.382 P 178

446.56 447 1.277 P 179

476.63 477.3 1.293 P 180

488.64 489.4 1.248 P 181

463.56 464.3 1.49 P 182

448.55 449.3 1.631 P 183

450.56 451.3 1.406 P 184

392.48 393.2 1.111 P 185

451.59 452.3 1.432 P 186

511.65 512.3 1.451 P 187

476.6 477.3 0.953 Q 188

493.59 494.3 1.456 P 189

501.56 502.3 1.938 P 190

493.59 1.593 D 191

437.52 438.3 1.162 P 192

492.6 493.3 1.832 P 193

506.63 507.3 1.384 P 194

506.63 507.3 1.562 P 195

494.62 495.4 1.565 P 196

491.66 492.4 1.982 P 197

492.6 493.3 1.661 P 198

448.59 449.3 1.624 P 199

448.59 449.3 1.45 P 200

490.67 491.4 1.676 P 201

503.65 504.4 1.346 P 202

461.61 462 1.451 P 203

500.69 501.4 1.726 P 204

500.69 501.4 1.437 P 205

501.68 502 1.333 P 206

504.68 505.3 1.659 P 207

504.68 505.4 1.413 P 208

472.59 473.3 1.394 P 209

472.59 473.3 1.32 P 210

460.63 461.3 1.415 P 211

476.63 477.3 1.518 P 212

434.56 435.3 1.322 P 213

405.51 406.2 1.055 P 214

437.56 438.3 1.35 P 215

450.6 451.3 1.798 P 216

424.56 425 1.558 P 217

492.6 493.3 1.333 P 218

451.55 452.3 1.21 P 219

449.58 450.3 1.313 P 220

491.62 492.4 1.308 P 221

508.6 509.3 1.532 P 222

494.58 495.3 1.419 P 223

478.57 1.756 P 224

478.57 479.3 1.465 P 225

506.63 507.4 1.692 P 226

504.61 505.3 1.348 P 227

478.62 479.3 1.394 P 228

464.59 465 1.371 P 229

492.64 493.3 1.833 P 230

448.59 449.3 1.385 P 231

476.6 477.3 1.886 P 232

504.65 505.4 1.678 P 233

460.6 461.3 1.58 P 234

490.67 491.4 1.924 P 235

445.62 446 1.535 P 236

445.62 446.3 1.504 P 237

473.63 474 1.494 P 238

486.64 487.4 2.289 P 239

486.64 487.3 1.888 P 240

524.66 525.4 1.505 P 241

502.66 503.4 1.233 P 242

474.61 475.4 1.605 P 243

474.61 475.4 1.337 P 244

492.64 493.4 1.821 P 245

500.65 501.3 1.546 P 246

500.65 501.3 1.26 P 247

486.71 487.4 1.625 P 248

432.57 433.3 1.246 P 249

432.57 433.3 1.367 P 250

476.6 477.3 1.626 P 251

422.55 423.2 1.768 P 252

490.61 491 1.429 P 253

463.56 464.2 1.241 P 254

505.6 506.3 1.34 P 255

463.56 464.3 1.428 P 256

435.55 436.3 1.269 P 257

485.56 486.3 2.006 P 258

479.6 480.4 1.303 P 259

492.6 493.2 1.584 P 260

476.64 477.4 1.269 P 261

462.62 463.3 2.006 P 262

446.57 447.3 1.303 P 263

462.62 463 1.727 P 264

505.64 506 1.406 P 265

487.65 488 1.545 P 266

520.65 503.3 1.532 P 267

476.6 477.3 1.966 P 268

460.63 461.4 1.321 P 269

502.66 503.4 1.584 P 270

502.66 503.4 1.303 P 271

492.64 493.4 1.3 P 272

432.57 433 1.529 P 273

446.56 447 1.335 P 274

446.56 447.3 1.32 P 275

474.61 475.4 1.378 P 276

474.61 475 1.251 P 277

458.65 459.4 1.255 P 278

489.62 490.3 1.525 P 279

443.6 444.3 1.466 P 280

470.63 471.4 1.99 P 281

521.68 522.3 1.15 Q 282

473.63 474.3 1 Q 283

475.64 476.4 1.191 Q 284

486.62 487.3 1.107 Q 285

550.73 551.3 1.828 P 286

484.65 485.4 1.209 Q 287

445.57 446.2 1.498 P 288

462.56 462.1 2.369 P 289

462.56 462.1 2.37 P 290

497.62 498.2 1.228 P 291

497 497 1.491 P 292

461.57 462.2 1.453 P 293

497 497.3 0.935 P 294

532.06 532.1 1.827 P 295

391.48 392.1 1.181 P 296

462.6 463.2 1.376 P 297

460.59 461.2 1.423 P 298

475.6 476.2 1.393 P 299

459.6 460.2 1.424 P 300

476.59 477.3 1.241 P 301

375.48 376 1.155 P 302

446.56 447.2 1.406 P 303

447.54 447.2 1.227 P 304

511.03 511.2 1.626 P 305

511.03 511.1 1.813 P 306

446.56 447.1 1.577 P 307

447.59 448.3 1.113 P 308

460.58 461.3 1.417 P 309

486.62 487 1.401 P 310

474.65 475 1.624 P 311

442.61 443.3 1.43 P 312

390.49 391.3 0.916 P 313

475.64 476.3 1.325 P 314

475.6 476.3 1.405 P 315

446.6 447.4 1.401 P 316

446.6 447.4 1.332 P 317

474.61 475 1.397 P 318

444.63 445.3 1.333 P 319

448.53 449.2 1.106 P 320

461.57 462.3 1.197 P 321

489.62 490 1.102 P 322

489.62 490.3 1.212 P 323

446.6 447.3 1.258 P 324

444.58 445.3 1.19 P 325

474.65 475 1.452 P 326

444.63 445.3 1.489 P 327

472.64 473 1.752 P 328

489.62 490.3 1.596 P 329

476.59 477.3 1.116 P 330

460.58 461.4 1.309 P 331

446.6 447 1.247 P 332

444.58 445.3 1.318 P 333

490.61 491.3 1.124 P 334

458.61 459 1.456 P 335

442.61 443.4 1.562 P 336

466.58 467 2.17 P 337

472.68 473.4 1.657 P 338

489.62 490.3 1.443 P 339

476.59 477.3 1.007 P 340

432.57 433.3 1.194 P 341

430.56 431.1 1.622 P 342

474.61 475 1.23 P 343

475.6 476.3 1.092 P 344

490.61 491.3 1.208 P 345

462.56 463.3 1.036 P 346

458.61 459 1.616 P 347

460.63 461.4 1.709 P 348

460.63 461 1.332 P 349

472.64 473 1.403 P 350

466.58 467 1.794 P 351

472.68 473.4 1.728 P

Example 3522-(4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-4-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)piperazin-1-yl)-N,N-dimethylacetamide

Intermediate 352A: tert-butyl4-(3-isopropyl-4-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)piperazine-1-carboxylate

tert-butyl5-(4-(tert-butoxycarbonyl)piperazin-1-yl)-3-isopropyl-4-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-c]pyridine-1-carboxylate(0.68 g, 1.163 mmol) was taken in a sealed tube and heated at 160° C.for 15 min to afford tert-butyl4-(3-isopropyl-4-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)piperazine-1-carboxylate (0.56 g, 1.152 mmol, 99% yield).LCMS retention time 1.64 min [L]. MS (E⁻) m/z: 485.4 (M+H).

Intermediate 352B: tert-butyl4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-4-methyl-TH-pyrrolo[2,3-c]pyridin-5-yl)piperazine-1-carboxylate

tert-butyl4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-4-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)piperazine-1-carboxylate(0.43 g, 0.854 mmol, 75% yield) was prepared as described in thepreparation of Intermediate 213I using tert-butyl4-(3-isopropyl-4-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)piperazine-1-carboxylate(0.55 g, 1.135 mmol) and6-bromo-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine (0.308 g, 1.362mmol) as the starting intermediates. LCMS retention time 1.99 min [L].MS (E⁻) m/z: 504.4 (M+H).

Intermediate 352C:6-(3-isopropyl-4-methyl-5-(piperazin-1-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl)-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine

6-(3-isopropyl-4-methyl-5-(piperazin-1-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl)-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine(0.31 g, 0.768 mmol, 90% yield) was prepared as described in thepreparation of Example 4 using tert-butyl4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-4-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)piperazine-1-carboxylate (0.43 g, 0.854 mmol) as the startingintermediate. LCMS retention time 0.95 min [L]. MS (E⁻) m/z: 404.4(M+H).

Example 352

2-(4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-4-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)piperazin-1-yl)-N,N-dimethylacetamide(16.9 mg, 0.035 mmol, 55.8% yield) was prepared as described in thepreparation of Example 2 using6-(3-isopropyl-4-methyl-5-(piperazin-1-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl)-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine(25 mg, 0.062 mmol) and 2-chloro-N,N-dimethylacetamide (15.06 mg, 0.124mmol) the starting intermediates. LCMS retention time 1.539 min [D4]. MSm/z: 489.3 [M+H]+; ¹H NMR (400 MHz, DMSO-d₆) δ 11.96-11.83 (m, 1H), 8.95(s, 1H), 8.52 (s, 1H), 8.49 (s, 1H), 4.40 (s, 2H), 3.42-3.26 (m, 9H),2.99 (s, 3H), 2.95 (s, 3H), 2.70 (s, 3H), 2.61 (s, 3H), 2.16-2.05 (m,3H), 1.24 (d, J=7.1 Hz, 3H), 1.02 (d, J=6.8 Hz, 3H).

Example 3536-(4-fluoro-3-isopropyl-5-(piperazin-1-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl)-8-methoxy-[1,2,4]triazolo[1,5-a]pyridine

Intermediate 353A:5-chloro-4-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridine

5-chloro-4-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridine(9.6 g, 31.9 mmol, 91% yield) was prepared as described in thepreparation of Intermediate 213A using5-chloro-4-fluoro-1H-pyrrolo[2,3-c]pyridine (6 g, 35.2 mmol) as thestarting material. LCMS retention time min 2.17[L]. MS (E⁻) m/z: 301.2(M+H).

Intermediate 353B:3-bromo-5-chloro-4-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridine

3-bromo-5-chloro-4-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridine (5.65 g, 14.88 mmol, 90% yield) as brown solid was prepared asdescribed in the preparation of Intermediate 213C using5-chloro-4-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridine (5 g, 16.62 mmol) as the startingintermediate. LCMS retention time 381.1 min [L]. MS (E⁻) m/z: (M+2H).

Intermediate 353C:5-chloro-4-fluoro-3-(prop-1-en-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridine

5-chloro-4-fluoro-3-(prop-1-en-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridine(6.0 g, 17.60 mmol, 84% yield) was prepared as described in thepreparation of Intermediate 213D using3-bromo-5-chloro-4-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridine(8.0 g, 21.07 mmol) and4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (3.54 g,21.07 mmol) as the starting intermediates. LCMS retention time 1.48 min[L]. MS (E⁻) m/z: 341.1 (M+H).

Intermediate 353D:5-chloro-4-fluoro-3-isopropyl-1-((2-trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridine

5-chloro-4-fluoro-3-isopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridine(5.82 g, 13.92 mmol, 79% yield) was prepared as described in thepreparation of Intermediate 213E using5-chloro-4-fluoro-3-(prop-1-en-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridine (6.0 g, 17.60 mmol) as the startingintermediate. LCMS retention time 1.61 min [L]. MS (E⁻) m/z: 343.5(M+H).

Intermediate 353E: tert-butyl4-(4-fluoro-3-isopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)piperazine-1-carboxylate

tert-butyl4-(4-fluoro-3-isopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1Hpyrrolo[2,3-c]pyridin-5-yl)piperazine-1-carboxylate (3.6 g, 7.31 mmol,84% yield) was prepared as described in the preparation of Intermediate213B using5-chloro-4-fluoro-3-isopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridine(3.000 g, 8.75 mmol) and tert-butyl piperazine-1-carboxylate (1.955 g,10.50 mmol) as the starting intermediates. LCMS retention time 1.81 min[L]. MS (E⁻) m/z: 493.9 (M+H).

Intermediate 353F: tert-butyl4-(4-fluoro-3-isopropyl-1H-pyrrolo[2,3-c]pyridin-5-yl)piperazine-1-carboxylate

tert-butyl4-(4-fluoro-3-isopropyl-1H-pyrrolo[2,3-c]pyridin-5-yl)piperazine-1-carboxylate(2.1 g, 5.79 mmol, 95% yield) was prepared as described in thepreparation of Intermediate 213F using tert-butyl4-(4-fluoro-3-isopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)piperazine-1-carboxylate(3.0 g, 6.09 mmol) as the starting intermediate. LCMS retention time1.81 min [L]. MS (E⁻) m/z: 363.2 (M+H).

Intermediate 353G: tert-butyl5-(4-(tert-butoxycarbonyl)piperazin-1-yl)-4-fluoro-3-isopropyl-1H-pyrrolo[2,3-c]pyridine-1-carboxylate

tert-butyl5-(4-(tert-butoxycarbonyl)piperazin-1-yl)-4-fluoro-3-isopropyl-1H-pyrrolo[2,3-c]pyridine-1-carboxylate(2.3 g, 4.97 mmol, 90% yield) was prepared according to the generalprocedure described in Intermediate 11 using tert-butyl4-(4-fluoro-3-isopropyl-1H-pyrrolo[2,3-c]pyridin-5-yl)piperazine-1-carboxylate(2 g, 5.52 mmol) as the starting intermediate. LCMS retention time 1.87min [L]. MS m/z: 463.4 [M+H]⁺.

Intermediate 353H: tert-butyl5-(4-(tert-butoxycarbonyl)piperazin-1-yl)-4-fluoro-3-isopropyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-c]pyridine-1-carboxylate

tert-butyl5-(4-(tert-butoxycarbonyl)piperazin-1-yl)-4-fluoro-3-isopropyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-c]pyridine-1-carboxylate(1.45 g, 2.464 mmol, 92% yield) was prepared according to the generalprocedure described in Intermediate 1L using tert-butyl5-(4-(tert-butoxycarbonyl)piperazin-1-yl)-4-fluoro-3-isopropyl-1H-pyrrolo[2,3-c]pyridine-1-carboxylate(1.24 g, 2.68 mmol) as the starting intermediate. LCMS retention time2.127 min [D]. MS m/z: 589.2 [M+H]⁺.

Intermediate 353I: tert-butyl5-(4-(tert-butoxycarbonyl)piperazin-1-yl)-4-fluoro-3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-pyrrolo[2,3-c]pyridine-1-carboxylate

tert-butyl5-(4-(tert-butoxycarbonyl)piperazin-1-yl)-4-fluoro-3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-pyrrolo[2,3-c]pyridine-1-carboxylate(0.85 g, 1.394 mmol, 70.7% yield) was prepared according to the generalprocedure described in Intermediate 1M using tert-butyl5-(4-(tert-butoxycarbonyl)piperazin-1-yl)-4-fluoro-3-isopropyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-c]pyridine-1-carboxylate(1.16 g, 1.971 mmol) as the starting intermediate. LCMS retention time1.37 min [L]. MS m/z: 610.5 [M+H]⁺.

Example 353

6-(4-fluoro-3-isopropyl-5-(piperazin-1-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl)-8-methoxy-[1,2,4]triazolo[1,5-a]pyridine(0.27 g, 0.653 mmol, 93% yield) was prepared according to the generalprocedure described in the preparation of Example 4 using tert-butyl5-(4-(tert-butoxycarbonyl)piperazin-1-yl)-4-fluoro-3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-pyrrolo[2,3-c]pyridine-1-carboxylate(0.43 g, 0.705 mmol) as the starting intermediate. LCMS retention time1.270 min [D4]. MS m/z: 410.3 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 11.79(br. s., 1H), 8.70 (d, J=1.2 Hz, 1H), 8.55 (s, 1H), 8.32 (d, J=1.5 Hz,1H), 7.18 (s, 1H), 4.07 (s, 3H), 3.28 (dd, J=7.3, 3.9 Hz, 1H), 3.18-3.11(m, 5H), 2.98-2.86 (m, 4H), 1.34 (d, J=6.8 Hz, 6H).

The following Example was prepared according to the general procedureused to prepare Example 353:

Ex. LCMS HPLC No. structure (M + H) RT method 354

424.3 0.91 L

Example 3556-(4-fluoro-3-isopropyl-5-(2,6-diazaspiro[3.3]heptan-2-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl)-8-methoxy-[1,2,4]triazolo[1,5-a]pyridine

Intermediate 355A: tert-butyl6-(4-fluoro-3-isopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate

tert-butyl6-(4-fluoro-3-isopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate(6.66 g, 13.20 mmol, 94% yield) was prepared as described in thepreparation of Intermediate 213B using5-chloro-4-fluoro-3-isopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridine(4.8 g, 14.00 mmol) and tert-butyl2,6-diazaspiro[3.3]heptane-2-carboxylate (3.33 g, 16.80 mmol) asstarting materials. LCMS retention time 1.69 min [L]. MS (E⁻) m/z: 505.7(M+H).

The following Intermediates were prepared according to the generalprocedure used to prepare Intermediate 355A:

LCMS HPLC Int. Structure (M + H) RT method 393A

493.9 1.81 L 393A

507.9 1.92 L

Intermediate 355B: tert-butyl6-(4-fluoro-3-isopropyl-1H-pyrrolo[2,3-c]pyridin-5-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate

tert-butyl6-(4-fluoro-3-isopropyl-1H-pyrrolo[2,3-c]pyridin-5-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate(5.0 g, 12.15 mmol, 92% yield) was prepared as described in thepreparation of Intermediate 213F using tert-butyl6-(4-fluoro-3-isopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate(6.66 g, 13.20 mmol) as a starting material. LCMS retention time 0.93min [L]. MS (E⁻) m/z: 375.3 (M+H).

Intermediate 355C: tert-butyl5-(6-(tert-butoxycarbonyl)-2,6-diazaspiro[3.3]heptan-2-yl)-4-fluoro-3-isopropyl-1H-pyrrolo[2,3-c]pyridine-1-carboxylate

tert-butyl5-(6-(tert-butoxycarbonyl)-2,6-diazaspiro[3.3]heptan-2-yl)-4-fluoro-3-isopropyl-1H-pyrrolo[2,3-c]pyridine-1-carboxylate(4 g, 8.43 mmol, 63.1% yield) was prepared as described in thepreparation of Intermediate 11 using tert-butyl6-(4-fluoro-3-isopropyl-1H-pyrrolo[2,3-c]pyridin-5-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate(5 g, 13.35 mmol) as a starting material. LCMS retention time 1.71 min[L]. MS (E⁻) m/z: 475.3 (M+H).

Intermediate 355D: tert-butyl5-(6-(tert-butoxycarbonyl)-2,6-diazaspiro[3.3]heptan-2-yl)-4-fluoro-3-isopropyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-c]pyridine-1-carboxylate

tert-butyl5-(6-(tert-butoxycarbonyl)-2,6-diazaspiro[3.3]heptan-2-yl)-4-fluoro-3-isopropyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-c]pyridine-1-carboxylate(4.5 g, 7.49 mmol, 89% yield) was prepared as described in thepreparation of Intermediate 1L using tert-butyl5-(6-(tert-butoxycarbonyl)-2,6-diazaspiro[3.3]heptan-2-yl)-4-fluoro-3-isopropyl-1H-pyrrolo[2,3-c]pyridine-1-carboxylate(4.0 g, 8.43 mmol) as the starting material. LCMS retention time 2.834min [D]. MS (E⁻) m/z: 601.4 (M+H).

Intermediate 355E: tert-butyl5-(6-(tert-butoxycarbonyl)-2,6-diazaspiro[3.3]heptan-2-yl)-4-fluoro-3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-pyrrolo[2,3-c]pyridine-1-carboxylate

tert-butyl5-(6-(tert-butoxycarbonyl)-2,6-diazaspiro[3.3]heptan-2-yl)-4-fluoro-3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-pyrrolo[2,3-c]pyridine-1-carboxylate(1.4 g, 2.252 mmol, 67.6% yield) was prepared as described in thepreparation of Intermediate 1M using tert-butyl5-(6-(tert-butoxycarbonyl)-2,6-diazaspiro[3.3]heptan-2-yl)-4-fluoro-3-isopropyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-c]pyridine-1-carboxylate(2.0 g, 3.33 mmol) and 6-bromo-8-methoxy-[1,2,4]triazolo[1,5-a]pyridine(0.835 g, 3.66 mmol) as starting materials. LCMS retention time 1.12 min[L]. MS (E⁻) m/z: 622.4 (M+H).

Example 355

6-(4-fluoro-3-isopropyl-5-(2,6-diazaspiro[3.3]heptan-2-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl)-8-methoxy-[1,2,4]triazolo[1,5-a]pyridine(0.55 g, 1.305 mmol, 62.4% yield) was prepared according to the generalprocedure described in the preparation of Example 4 using tert-butyl5-(6-(tert-butoxycarbonyl)-2,6-diazaspiro[3.3]heptan-2-yl)-4-fluoro-3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-pyrrolo[2,3-c]pyridine-1-carboxylate(1.3 g, 2.091 mmol) in DCM (15 mL) as starting material. LCMS retentiontime 0.83 min [L]. MS (E⁻) m/z: 422.3 (M+H).

Example 3562-(6-(4-fluoro-3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)-2,6-diazaspiro[3.3]heptan-2-yl)-N-methylacetamide

2-(6-(4-fluoro-3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)-2,6-diazaspiro[3.3]heptan-2-yl)-N-methylacetamide(3.1 mg, 174 6.04 μmol, 8.49% yield) was prepared as described in thepreparation of Example 2 using6-(4-fluoro-3-isopropyl-5-(2,6-diazaspiro[3.3]heptan-2-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl)-8-methoxy-[1,2,4]triazolo[1,5-a]pyridine(30 mg, 0.071 mmol) and 2-chloro-N-methylacetamide (11.48 mg, 0.107mmol) as the starting intermediates. LCMS retention time 1.322 m [P]. MSm/z: 493.3 [M+H]+; ¹H NMR (400 MHz, DMSO-d₆) δ=11.62 (d, J=1.2 Hz, 1H),8.69 (s, 1H), 8.55 (s, 1H), 8.22 (d, J=1.7 Hz, 1H), 7.70-7.55 (m, 1H),7.17 (s, 1H), 4.11-4.03 (m, 8H), 3.43 (s, 4H), 3.28-3.20 (m, 1H), 3.01(s, 2H), 2.60 (d, J=4.9 Hz, 2H), 1.33 (d, J=7.3 Hz, 6H).

The following Examples were prepared according to the general procedureused to prepare Example 356:

Ex. LCMS HPLC No. Structure (M + H) RT method 357

528.2 1.397 D4 358

467.3 1.486 D4 359

481.3 1.558 D4 360

495.3 1.62 D4 361

468.3 1.699 D4 362

516.3 1.617 D4 363

537.3 1.616 D4 364

482.3 1.781 D4 365

449.2 1.558 D4 366

492.2 2.023 D4

Example 3671-(6-(4-fluoro-3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)-2,6-diazaspiro[3.3]heptan-2-yl)-2-morpholinoethan-1-one

1-(6-(4-fluoro-3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)-2,6-diazaspiro[3.3]heptan-2-yl)-2-morpholinoethan-1-one(2.3 mg, 4.19 μmol, 5.89% yield) was prepared as described in thepreparation of Example 5 using6-(4-fluoro-3-isopropyl-5-(2,6-diazaspiro[3.3]heptan-2-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl)-8-methoxy-[1,2,4]triazolo[1,5-a]pyridine(30 mg, 0.071 mmol) and 2-morpholinoacetic acid (15.50 mg, 0.107 mmol)as the starting intermediates. LCMS retention time 1.407 min [P]. MSm/z: 549.3 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ=11.64 (s, 1H), 8.69 (s,1H), 8.55 (s, 1H), 8.23 (d, J=1.7 Hz, 1H), 7.18 (s, 1H), 4.41 (s, 2H),4.13 (s, 4H), 4.08 (s, 5H), 3.59 (br d, J=3.4 Hz, 6H), 2.99 (br d, J=1.7Hz, 2H), 2.43 (br d, J=2.2 Hz, 3H), 1.33 (d, J=7.1 Hz, 6H).

The following Example was prepared according to the general procedureused to prepare Example 367:

Ex. LCMS HPLC No. Structure (M + H) RT method 368

495.3 1.453 D4

Example 3696-(4-fluoro-3-isopropyl-5-(6-(oxetan-3-yl)-2,6-diazaspiro[3.3]heptan-2-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl)-8-methoxy-[1,2,4]triazolo[1,5-a]pyridine

6-(4-fluoro-3-isopropyl-5-(6-(oxetan-3-yl)-2,6-diazaspiro[3.3]heptan-2-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl)-8-methoxy-[1,2,4]triazolo[1,5-a]pyridine(8.2 mg, 0.017 mmol, 23.88% yield) was prepared as described in thepreparation of Example 42 using6-(4-fluoro-3-isopropyl-5-(2,6-diazaspiro[3.3]heptan-2-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl)-8-methoxy-[1,2,4]triazolo[1,5-a]pyridine(30 mg, 0.071 mmol) and oxetan-3-one (10.26 mg, 0.142 mmol) as thestarting intermediates. LCMS retention time 1.410 min [P]. MS m/z: 478.2[M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ=11.62 (s, 1H), 8.69 (d, J=0.7 Hz,1H), 8.55 (s, 1H), 8.22 (d, J=2.0 Hz, 1H), 7.17 (s, 1H), 4.55 (t, J=6.5Hz, 2H), 4.35 (t, J=5.7 Hz, 2H), 4.07 (s, 7H), 3.73-3.64 (m, 1H), 3.39(s, 4H), 3.25 (dt, J=4.6, 6.8 Hz, 1H), 1.33 (d, J=7.1 Hz, 6H).

The following Examples were prepared according to the general procedureused to prepare Example 369:

Ex. LCMS HPLC No. Structure (M + H) RT method 370

506.2  1.429 D4 371

520.3  1.402 D4 372

478.3  1.415 D4 373

464.3  1.282 D4 374

476.3  1.332 D4 375

490.3  1.494 D4 376

506.3  1.459 D4 377

547.4  1.318 D4 378

436.2  1.166 D4 379

450.2  1.240 D4 380

464.2  1.376 D4 381

476.2  1.467 D4 382

466.3 11.642 D4 383

508.3 11.872 D4 384

452.3 11.619 D4 385

494.3 11.847 D4 386

494.3 11.661 D4 Isomer-1 387

494.3 11.663 D4 Isomer-2 388

535.3 11.302 D4 389

438.3 11.401 D4 390

464.2 11.607 D4 391

464.2 11.722 D4

Example 3926-(4-fluoro-3-isopropyl-5-(2,6-diazaspiro[3.3]heptan-2-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl)-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine

Intermediate 392A: tert-butyl6-(4-fluoro-3-isopropyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate

tert-Butyl5-(6-(tert-butoxycarbonyl)-2,6-diazaspiro[3.3]heptan-2-yl)-4-fluoro-3-isopropyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-c]pyridine-1-carboxylate(2.3 g, 3.83 mmol) was placed in a sealed tube and heated at 160° C. for15 min. LCMS retention time 1.33 min [L]. MS (E⁻) m/z: 501.4 (M+H).

Intermediate 392B: tert-butyl6-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-fluoro-3-isopropyl-1H-pyrrolo[2,3-c]pyridin-5-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate

To a solution of tert-butyl6-(4-fluoro-3-isopropyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate(1.9 g, 3.80 mmol) and6-bromo-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine (0.944 g, 4.18 mmol)in mixture of THF (30 mL) and water (3 mL) was added tripotassiumphosphate (2.015 g, 9.49 mmol). The reaction mixture was purged withnitrogen for 5 mins, thenchloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(0.299 g, 0.380 mmol) was added. The reaction mixture was purged againfor 2 mins and then heated in a sealed tube at 75° C. for 1 h. Thereaction mixture was filtered through Celite and diluted with EtOAc (50mL) and washed with water (10 mL), and brine solutions (10 mL). Theorganic layer was dried over Na₂SO₄, filter and concentrated to givecrude compound which was purified over silica gel eluting 5% MeOH inDCM. LCMS retention time 0.93 min [L]. MS (E⁻) m/z: 520.3 (M+H).

The following Intermediates were prepared according to the generalprocedure used to prepare Intermediate 392B:

Int. LCMS HPLC No. Structure (M + H) RT method 393B

508.2 3.411 D 394B

522.4 2.05 L

Example 392

6-(4-fluoro-3-isopropyl-5-(2,6-diazaspiro[3.3]heptan-2-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl)-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine(0.79 g, 1.751 mmol, 79% yield) was prepared as described in thepreparation of Example 4 using tert-butyl6-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-fluoro-3-isopropyl-1H-pyrrolo[2,3-c]pyridin-5-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate(1.15 g, 2.213 mmol) as the starting intermediate. LCMS retention time1.163 min [D4]. MS (E⁻) m/z: 420.1 (M+H). ¹H NMR (400 MHz, DMSO-d₆) δppm 11.38-11.56 (m, 1H) 8.88 (s, 1H) 8.50 (s, 1H) 8.12-8.22 (m, 1H)4.01-4.15 (m, 4H) 3.76 (s, 4H) 2.81 (td, J=7.09, 3.67 Hz, 1H) 2.59 (s,3H) 2.11-2.17 (m, 3H) 1.77 (s, 1H) 1.23 (br t, J=6.72 Hz, 6H).

The following Examples were prepared according to the general procedureused to prepare Example 392:

LCMS HPLC Ex. No. Structure (M + H) RT method 393

408.3 1.356 D4 394

507.9 1.92 L

Example 3952-(6-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-fluoro-3-isopropyl-1H-pyrrolo[2,3-c]pyridin-5-yl)-2,6-diazaspiro[3.3]heptan-2-yl)-N-methylacetamide

2-(6-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-fluoro-3-isopropyl-1H-pyrrolo[2,3-c]pyridin-5-yl)-2,6-diazaspiro[3.3]heptan-2-yl)-N-methylacetamide(3.9 mg, 7.95 μmol, 11% yield) was prepared as described in thepreparation of Example 2 using6-(4-fluoro-3-isopropyl-5-(2,6-diazaspiro[3.3]heptan-2-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl)-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine(30 mg, 0.072 mmol) and 2-chloro-N-methylacetamide (11.54 mg, 0.107mmol) as the starting intermediates. LCMS retention time 1.057 min [D4].MS m/z: 491.3 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.44 (d, J=0.98Hz, 1H) 8.88 (s, 1H) 8.50 (s, 1H) 8.18 (d, J=1.96 Hz, 1H) 7.67-7.77 (m,1H) 4.02-4.13 (m, 4H) 3.50-3.61 (m, 3H) 3.11-3.21 (m, 2H) 2.81 (dtd,J=13.72, 6.89, 6.89, 3.79 Hz, 1H) 2.58-2.63 (m, 6H) 2.55 (s, 1H) 2.14(s, 3H) 1.23 (t, J=6.60 Hz, 6H).

The following Examples were prepared according to the general procedureused to prepare Example 395:

Ex. LCMS HPLC No. Structure (M + H) RT method 396

526.2 1.486 D4 397

459.2 1.609 D4 398

514.3 1.709 D4

Example 3991-(6-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-fluoro-3-isopropyl-1H-pyrrolo[2,3-c]pyridin-5-yl)-2,6-diazaspiro[3.3]heptan-2-yl)-2-morpholinoethan-1-one

1-(6-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-fluoro-3-isopropyl-1H-pyrrolo[2,3-c]pyridin-5-yl)-2,6-diazaspiro[3.3]heptan-2-yl)-2-morpholinoethan-1-one(9.5 mg, 0.017 mmol, 23.6% yield) was prepared as described in thepreparation of Example 5 using6-(4-fluoro-3-isopropyl-5-(2,6-diazaspiro[3.3]heptan-2-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl)-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine(30 mg, 0.072 mmol) and 2-morpholinoacetic acid (15.57 mg, 0.107 mmol)as the starting intermediates. LCMS retention time 1.470 min [P]. MSm/z: 547.3 [M+H]+; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.46 (d, J=1.71 Hz,1H) 8.89 (s, 1H) 8.50 (s, 1H) 8.19 (d, J=1.96 Hz, 1H) 4.40 (s, 2H)4.05-4.18 (m, 6H) 3.56-3.63 (m, 4H) 2.94-3.03 (m, 2H) 2.76-2.86 (m, 1H)2.60 (s, 3H) 2.39-2.47 (m, 4H) 2.14 (s, 3H) 1.20-1.27 (m, 6H).

Example 4006-(4-fluoro-3-isopropyl-5-(6-(oxetan-3-yl)-2,6-diazaspiro[3.3]heptan-2-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl)-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine

6-(4-fluoro-3-isopropyl-5-(6-(oxetan-3-yl)-2,6-diazaspiro[3.3]heptan-2-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl)-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine(10.4 mg, 0.021 mmol, 28.7% yield) was prepared as described in thepreparation of Example 42 using6-(4-fluoro-3-isopropyl-5-(2,6-diazaspiro[3.3]heptan-2-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl)-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine(30 mg, 0.072 mmol) and oxetan-3-one (10.31 mg, 0.143 mmol) as thestarting intermediates. LCMS retention time 1.498 min [D4]. MS m/z:476.2 [M+H]+; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.41-11.50 (m, 1H) 8.89(s, 1H) 8.50 (s, 1H) 8.17-8.23 (m, 1H) 4.73-4.79 (m, 1H) 4.53-4.64 (m,2H) 4.33-4.43 (m, 2H) 4.03-4.11 (m, 3H) 3.91-3.98 (m, 1H) 3.65-3.76 (m,1H) 3.41 (br s, 3H) 2.76-2.87 (m, 1H) 2.59 (s, 3H) 2.14 (s, 3H) 1.23 (brt, J=6.60 Hz, 6H).

The following Examples were prepared according to the general procedureused to prepare Example 400:

Ex. LCMS HPLC No. Structure (M + H) RT method 401

504.3 1.511 D4 402

476.3 1.586 D4 403

462.3 1.128 D4 404

488.3 1.623 D4 405

504.3 1.608 D4 406

545.3 1.408 D4 407

434.2 1.262 D4 408

448.2 1.322 D4 409

464.3 1.738 D4 410

492.3 1.949 D4 411

506.3 1.968 D4 412

450.3 1.702 D4

The following Examples were prepared according to the general procedureused to prepare Example 352

Ex. LCMS HPLC No. Structure (M + H) RT method 413

475.3 1.542 D4 414

461.3 1.480 D4 415

510.2 2.176 D

Example 4161-(4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-4-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)piperazin-1-yl)-2-(dimethylamino)ethan-1-one

1-(4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-4-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)piperazin-1-yl)-2-(dimethylamino)ethan-1-one(10 mg, 0.020 mmol, 16.35% yield) was prepared as described in thepreparation of Example 5 using6-(3-isopropyl-4-methyl-5-(piperazin-1-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl)-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine(50 mg, 0.124 mmol) and dimethylglycine (25.6 mg, 0.248 mmol) as thestarting intermediates. LCMS retention time 1.939 min [D]. MS m/z: 489.2[M+H]+; ¹H NMR (400 MHz, DMSO-d₆) δ 11.30 (s, 1H), 8.85 (s, 1H), 8.46(s, 1H), 8.29 (s, 1H), 3.99-4.16 (m, 1H), 3.56-3.83 (m, 4H), 3.05-3.22(m, 3H), 2.80-3.03 (m, 6H), 2.63-2.71 (m, 5H), 2.30 (t, J=2.01 Hz, 1H),2.20 (s, 3H), 2.08 (s, 3H), 1.19 (d, J=7.03 Hz, 3H), 0.98 (d, J=7.03 Hz,3H).

Example 4176-(3-isopropyl-4-methyl-5-(4-(oxetan-3-yl)piperazin-1-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl)-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine

6-(3-isopropyl-4-methyl-5-(4-(oxetan-3-yl)piperazin-1-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl)-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine(16.3 mg, 0.033 mmol, 66.8% yield) was prepared as described in thepreparation of Intermediate 2C with6-(3-isopropyl-4-methyl-5-(piperazin-1-yl)-1H-pyrrolo[2,3-c]pyridin-2-yl)-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine(20 mg, 0.050 mmol) and oxetan-3-one (14.29 mg, 0.198 mmol) the startingintermediate. LCMS retention time 1.652 min [D4]. MS m/z: 460.3 [M+H]+;¹H NMR (400 MHz, DMSO-d₆) δ=12.02-11.82 (m, 1H), 8.95 (s, 1H), 8.52 (s,1H), 8.49 (s, 1H), 4.86-4.76 (m, 4H), 4.54-4.42 (m, 1H), 3.87 (br d,J=4.9 Hz, 1H), 3.37-3.26 (m, 8H), 2.71 (s, 3H), 2.61 (s, 3H), 2.14-2.07(m, 3H), 1.24 (d, J=7.1 Hz, 3H), 1.02 (d, J=7.1 Hz, 3H).

The following Examples were prepared according to the general procedureused to prepare Example 417:

Ex. LCMS HPLC No. Structure (M + H) RT method 418

488.3 1.630 D4 419

502.3 1.790 D4

Example 4201-(3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)piperidin-4-amine

Intermediate 420A: tert-butyl(1-(4-methyl-5-nitropyridin-2-yl)piperidin-4-yl)carbamate

tert-butyl (1-(4-methyl-5-nitropyridin-2-yl)piperidin-4-yl)carbamate (1g, 2.91 mmol, 63.2% yield) was prepared as described in the preparationof Intermediate 6A using 2-bromo-4-methyl-5-nitropyridine (1 g, 4.61mmol) and tert-butyl piperidin-4-ylcarbamate (0.923 g, 4.61 mmol) asstarting material. LCMS retention time 1.41 min [B]. MS (E⁻) m/z: 335.5(M−H).

Intermediate 420B:tert-butyl(E)-(1-(4-(2-(dimethylamino)vinyl)-5-nitropyridin-2-yl)piperidin-4-yl)carbamate

(E)-tert-butyl(1-(4-(2-(dimethylamino)vinyl)-5-nitropyridin-2-yl)piperidin-4-yl)carbamate (13 g, 31.9 mmol, 46% yield) was prepared as described in thepreparation of Intermediate 6B using tert-butyl(1-(4-methyl-5-nitropyridin-2-yl)piperidin-4-yl) carbamate (23 g, 68.4mmol) and 1,1-dimethoxy-N,N-dimethylmethanamine (45.8 mL, 342 mmol) asthe starting intermediates. LCMS retention time 1.38 min [B], MS (E*)m/z: 392.6 (M+H).

Intermediate 420C: tert-butyl(1-(1H-pyrrolo[2,3-c]pyridin-5-yl)piperidin-4-yl) carbamate

tert-butyl (1-(1H-pyrrolo[2,3-c]pyridin-5-yl)piperidin-4-yl)carbamate(13 g, 27.5 mmol, 71.8% yield) was prepared as described in thepreparation of intermediate 6C using tert-butyl (E)-tert-butyl4-(4-(2-(dimethylamino)vinyl)-5-nitropyridin-2-yl)piperazine-1-carboxylate (15 g, 39.7 mmol) as the starting intermediate.LCMS retention time 1.04 min [B], MS m/z: 317.5 (M+H).

Intermediate 420D: tert-butyl(1-(3-bromo-1H-pyrrolo[2,3-c]pyridin-5-yl)piperidin-4-yl) carbamate

tert-butyl(1-(3-bromo-1H-pyrrolo[2,3-c]pyridin-5-yl)piperidin-4-yl)carbamate (3 g,7.59 mmol, 80% yield) was prepared as described in the preparation ofIntermediate 6D using tert-butyl(1-(1H-pyrrolo[2,3-c]pyridin-5-yl)piperidin-4-yl)carbamate (3 g, 9.48mmol) as the starting intermediate. LCMS retention time 1.28 min [B], MS(E⁻) m/z: 397.4 (M+2H).

Intermediate 420E:tert-butyl3-bromo-5-(4-((tert-butoxycarbonyl)amino)piperidin-1-yl)-1H-pyrrolo[2,3-c]pyridine-1-carboxylate

tert-butyl3-bromo-5-(4-((tert-butoxycarbonyl)amino)piperidin-1-yl)-1H-pyrrolo[2,3-c]pyridine-1-carboxylate(2 g, 4.04 mmol, 80% yield) was prepared as described in the preparationof Intermediate 6E using tert-butyl(1-(3-bromo-1H-pyrrolo[2,3-c]pyridin-5-yl)piperidin-4-yl) carbamate (2g, 5.06 mmol) as the starting intermediate. LCMS retention time 1.64 min[B], MS (E⁻) m/z: 495.3 (M+H).

Intermediate 420F:tert-butyl5-(4-((tert-butoxycarbonyl)amino)piperidin-1-yl)-3-(prop-1-en-2-yl)-1H-pyrrolo[2,3-c]pyridine-1-carboxylate

tert-butyl5-(4-((tert-butoxycarbonyl)amino)piperidin-1-yl)-3-(prop-1-en-2-yl)-1H-pyrrolo[2,3-c]pyridine-1-carboxylate(1.6 g, 3.50 mmol, 83% yield) was prepared as described in thepreparation of Intermediate 6F using tert-butyl3-bromo-5-(4-((tert-butoxycarbonyl)amino)piperidin-1-yl)-1H-pyrrolo[2,3-c]pyridine-1-carboxylate(2.1 g, 4.24 mmol) as the starting intermediate. LCMS retention time1.30 min [B], MS (E⁻) m/z: 457.3 (M+H).

Intermediate 420G: tert-butyl5-(4-((tert-butoxycarbonyl)amino)piperidin-1-yl)-3-isopropyl-1H-pyrrolo[2,3-c]pyridine-1-carboxylate

tert-butyl5-(4-((tert-butoxycarbonyl)amino)piperidin-1-yl)-3-isopropyl-1H-pyrrolo[2,3-c]pyridine-1-carboxylate(1.6 g, 3.49 mmol, 88% yield) was prepared as described in thepreparation of Intermediate 6G using tert-butyl5-(4-((tert-butoxycarbonyl)amino)piperidin-1-yl)-3-(prop-1-en-2-yl)-1H-pyrrolo[2,3-c]pyridine-1-carboxylate(1.8 g, 3.94 mmol) as the starting intermediate. LCMS retention time1.78 min [B], MS (E⁺) m/z: 459.6 (M+H).

Intermediate 420H: tert-butyl5-(4-((tert-butoxycarbonyl)amino)piperidin-1-yl)-3-isopropyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-c]pyridine-1-carboxylate

tert-butyl 5-(4-((tert-butoxycarbonyl)amino)piperidin-1-yl)-3-isopropyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-c]pyridine-1-carboxylate(280 mg, 0.053 mmol, 4.03% yield) was prepared as described in thepreparation of Intermediate 61 using tert-butyl5-(4-((tert-butoxycarbonyl)amino)piperidin-1-yl)-3-isopropyl-1H-pyrrolo[2,3-c]pyridine-1-carboxylate(600 mg, 1.308 mmol as the starting intermediate. LCMS retention time2.10 min [B], MS (E⁻) m/z: 586.8 (M+H).

Intermediate 420I: tert-butyl5-(4-((tert-butoxycarbonyl)amino)piperidin-1-yl)-3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-pyrrolo[2,3-c]pyridine-1-carboxylate

tert-butyl-5-(4-((tert-butoxycarbonyl)amino)piperidin-1-yl)-3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-pyrrolo[2,3-c]pyridine-1-carboxylate (200 mg, 0.023mmol) was prepared as described in the preparation of Intermediate 6Jusing tert-butyl5-(4-((tert-butoxycarbonyl)amino)piperidin-1-yl)-3-isopropyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-c]pyridine-1-carboxylate(523 mg, 0.895 mmol) and6-bromo-8-methoxy-[1,2,4]triazolo[1,5-a]pyridine (245 mg, 1.074 mmol) asthe starting intermediates. LCMS retention time 1.57 min [B], MS (E⁻)m/z: 606.6 (M+H).

Example 420

1-(3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)piperidin-4-amine(145 mg, 0.318 mmol) was prepared according to the general proceduredescribed in Example 4 using tert-butyl 5-(4-((tert-butoxycarbonyl)amino)piperidin-1-yl)-3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-pyrrolo[2,3-c]pyridine-1-carboxylate(200 mg, 0.330 mmol) as starting material intermediate. LCMS retentiontime 0.68 min [B], MS (E⁺) m/z: 406.5 (M+H);

The following examples were prepared according to the general proceduresdescribed in the above examples.

Ex. Obs. QC No. Structure MS Ion RT Method 421

535.3 1.59 E 422

493.3 1.41 E 423

535.3 1.56 E 424

466.3 1.66 E 425

486.2 1.67 E 426

480.3 1.11 E 427

450.2 1.55 E 428

493.3 1.57 E 429

465.2 1.43 E 430

462.3 1.75 E 431

492.1 1.64 E 432

478.3 2.51 E 433

436.3 1.54 E 434

502.0 1.95 E 435

505.0 1.34 E 436

438.2 1.39 E 437

466.2 1.64 E 438

551.2 1.49 E 439

509.3 1.31 E 440

480.3 1.56 E 441

478.3 1.82 E 442

478.2 1.63 E 443

466.3 1.52 E 444

482.3 1.57 E 445

495.3 1.45 E 446

509.3 1.53 E 447

481.2 1.38 E 448

551.2 1.48 E 449

506.2 2.03 E 450

530.3 1.52 E 451

549.3 1.35 E 452

508.3 1.54 E 453

480.2 1.98 E 454

436.3 1.51 E 455

464.0 1.78 E 456

506.3 1.68 E 457

478.0 1.65 E 458

476.0 1.9 E 459

476.0 1.77 E 460

478.0 2.14 E 461

464.3 1.61 E 462

547.0 1.45 E 463

528.0 1.08 F 464

479.0 0.99 F 465

493.3 1.03 F 466

507.3 1.61 E 467

461.3 1.72 E 468

504.3 2.18 E 469

549.3 1.6 E 470

507.3 1.43 E 471

549.3 1.61 E 472

480.3 1.12 Fwhich induce the production of SEAP. After a 22 hour incubation at 37°C., 500 CO₂, SEAP levels are determined with the addition of HEK-Blue™Detection reagent (Invivogen), a cell culture medium that allows fordetection of SEAP, according to manufacturer's specifications. Thepercent inhibition is determined as the 00 reduction in the HEK-Bluesignal present in wells treated with agonist plus DMSO alone compared towells treated with a known inhibitor.

TABLE 2 TLR7/8/9 Reporter Assay Data (NT = not tested) TLR7 TLR8 TLR9TLR7 TLR8 TLR9 Ex. IC₅₀ IC₅₀ IC₅₀ Ex. IC₅₀ IC₅₀ IC₅₀ No. (nM) (nM) (nM)No. (nM) (nM) (nM) 1 4.7 89 550 234 13 2.6 733 2 1.6 14 398 235 0.24 1.02207 3 3.2 11 1582 236 0.66 1.1 939 4 NT 973 13083 237 1.6 0.95 2072 59.5 100 250 238 62 21 28464 6 0.61 1.4 664 239 2.6 2.6 15894 7 1.5 0.56168 240 0.96 0.39 2777 8 6638 15946 258 241 3.5 11 285 9 551 8225 26 24211 14 401 10 5.6 19 896 243 0.79 4.8 430 11 1.6 8.3 91 244 8.9 16 583 1253 273 866 245 6.3 47 257 13 6.5 6.8 2783 246 2.0 17 705 14 3.9 3.413016 247 16 10 718 15 3.5 1.6 13498 248 5.7 6.8 396 16 4.7 26 1286 24912 12 1446 17 1.3 1.6 1861 250 3.2 3.4 4773 18 0.76 2.6 1790 251 15 2314850 19 2.0 3.0 1758 252 6.4 5.2 3360 20 2.5 4.3 6546 253 0.97 0.772859 21 2.0 2.7 3338 254 1.5 0.55 3011 22 6.2 1.8 4250 255 0.50 0.4914492 23 2.6 3.4 147 256 1.4 1.2 15352 24 9.7 39 279 257 5.3 6.4 3602325 2.3 7.2 188 258 0.77 0.35 6015 26 3.1 6.9 633 259 2.1 2.6 16752 27 4986 477 260 1.4 1.7 837 28 13 26 608 261 0.61 1.1 1271 29 4.3 4.7 1696262 1.3 4.2 1328 30 4.7 7.7 855 263 1.9 4.1 5654 31 2.1 6.2 132 264 0.690.16 1643 32 40 124 279 265 0.36 0.42 1025 33 1.4 6.9 134 266 26 23 203534 2.5 2.0 1506 267 6.9 1.9 16699 35 1.7 2.8 154 268 4.8 17 757 36 19 48208 269 4.4 6.4 205 37 3.3 4.4 409 270 2.6 3.2 392 38 2.8 12 13055 2711.6 4.2 333 39 6.4 16 5530 272 7.0 22 391 40 9.9 11 8313 273 8.6 16 37641 36 158 >50000 274 42 35 648 42 1.6 0.59 9177 275 35 37 845 43 1.00.60 12749 276 7.7 1.2 114 44 0.63 0.36 2766 277 5.5 13 265 45 2.2 1.92766 278 0.79 0.58 1104 46 0.98 1.6 NT 279 0.65 1.5 1111 47 5.2 1.5 2580280 1.3 1.2 2503 48 12 13 9533 281 16 43 36393 49 0.46 0.62 2426 282 1.10.97 1068 50 0.76 0.83 1007 283 0.46 0.27 1617 51 0.74 0.58 2773 284 8.314 23513 52 0.98 0.42 1857 285 1.3 1.6 1868 53 0.50 2.0 1391 286 2.2 2.22858 54 0.90 0.30 935 287 2.0 16 718 55 1.3 1.3 769 288 27 8.5 2866 561.8 1.5 1007 289 3.7 58 14030 57 4.9 19 682 290 20 7.1 >50000 58 60 23692 291 3.0 4.9 494 59 15 4.7 197 292 7.0 47 303 60 5.0 1.2 502 293 3.14.7 29055 61 28 35 346 294 3.0 4.7 7634 62 5.1 21 417 296 3.3 5.4 132 6311 11 2992 297 >3125 >3125 17861 64 4.2 1.5 2794 298 14 75 459 65 2.25.6 3318 299 2.9 25 356 66 2.1 4.9 3623 300 13 1.6 11926 67 9.1 11 5799301 >3125 >3125 2681 68 NT NT 5289 302 1586 >3125 >50000 69 0.55 0.554053 303 19 12 >50000 70 0.23 0.78 3998 304 1.5 2.2 505 71 0.41 0.653608 305 2.5 1.4 2829 72 1.5 1.3 6085 306 3.9 16 786 73 0.87 0.77 2960307 3.0 0.85 657 74 1.7 0.77 694 308 7.9 25 159 75 2.5 5.6 447 309 7.349 133 76 0.58 3.8 959 310 13 32 640 77 2.7 4.5 403 312 8.5 114 920 784.3 11 8618 313 2.9 0.27 2416 79 3.0 3.6 842 314 4.3 1.5 3705 80 0.160.60 1833 315 7.6 47 166 81 0.15 0.61 2167 316 9.5 33 80 82 0.18 0.361465 317 2.1 7.1 34 83 1.3 1.4 9103 318 6.0 21 846 85 2.6 1.1 924 319 123.7 14449 86 0.37 0.43 1127 320 4.4 2.0 3007 87 0.33 1.0 701 321 2.80.64 1009 88 0.62 0.28 322 322 2.1 0.23 1452 89 6.5 4.9 435 323 4.5 20258 90 20 31 1395 324 3.0 20 283 91 40 27 676 325 2.4 12 512 92 34 32548 326 14 78 1218 93 18 37 2826 327 7.1 17 771 95 41 35 1383 328 11 601392 96 24 7.7 294 329 7.5 7.4 647 97 2.5 7.4 1080 330 1.1 5.5 255 984.7 14 1199 331 263 637 3304 99 0.49 0.41 3976 332 7.7 56 154 100 0.800.25 2336 333 5.4 4.3 1061 101 1.2 0.66 4137 334 0.35 1.4 452 102 0.340.24 2824 335 4.3 42 669 103 0.86 0.48 5916 336 8.8 36 3997 104 3.6 1.75296 337 3.9 4.0 777 105 0.22 0.59 2249 338 3.4 30 1109 106 4.9 5.0 1946339 12 28 677 107 3.6 4.5 2055 340 1274 708 11475 108 2.1 4.0 2764 3413.2 21 1031 109 0.61 1.7 1665 342 3.8 8.3 224 110 2.0 1.3 1163 343 28190 217 111 1.0 0.48 2999 344 1.7 3.5 257 112 1.6 2.3 1880 345 11 13 712113 0.72 0.57 510 346 3.3 14 750 114 4.8 6.6 17394 347 3.9 30 790 1151.4 2.4 15793 348 3.5 9.0 468 116 10 42 766 349 1.1 3.6 344 117 28 41868 350 1.4 4.7 1082 118 8.6 1.4 294 351 11 5.4 345 119 8.1 11 558 35214 0.73 19800 120 2.3 2.0 71 353 0.61 1.4 2526 121 2.7 5.9 759 354 1.69.9 3432 122 14 10 400 355 33 22 5593 123 26 31 1113 356 15 6.1 18544124 0.38 0.65 905 357 21 10 37404 125 3.1 6.5 7031 358 3.6 3.8 >50000126 8.2 3.2 2531 359 2.5 2.7 >50000 127 47 150 >50000 360 2.9 1.5 23031128 1.9 1.4 2477 361 3.8 0.76 4852 129 0.75 0.15 5903 362 4.9 4.0 NT 1301.3 0.76 5250 363 NT 3.7 43685 131 5.0 7.9 11424 364 2.7 0.38 8704 1323.4 5.0 2130 365 0.42 0.51 1490 133 0.52 1.2 1356 366 3.8 39 16209 1340.98 0.27 1025 367 159 52 >50000 135 0.24 0.48 6501 368 1.3 2.3 5886 1360.41 0.32 620 369 27 23 >50000 137 0.63 0.90 3163 370 19 174 10349 1380.26 0.49 1904 371 9.0 5.9 5477 139 1.1 1.0 1029 372 7.9 440 5441 1400.53 1.4 3047 373 8.1 7.1 5815 141 27 25 482 374 6.0 39 5470 142 13 39282 375 17 >3125 7209 143 33 33 683 376 9.5 >3125 6005 144 14 14 1252377 16 16 1413 145 9.1 11 506 378 6.0 3.4 5108 146 1.1 0.46 6659 379 4.02.3 3632 147 0.62 0.27 2059 380 5.6 7.8 1479 148 1.1 1.7 1171 381 9.9 112579 149 3.6 5.1 13082 382 4.5 18 >50000 150 3.4 5.3 6057 383 2.7 0.315394 151 1.1 4.4 768 384 0.96 0.55 3263 152 5.0 6.4 4090 385 4.1 1.442122 153 8.8 5.2 3826 386 26 6.8 >50000 154 4.0 4.4 1225 387 3313 >50000 155 7.3 5.0 6312 388 2.7 0.81 1892 156 0.79 0.26 6429 389 1.10.38 6162 157 0.80 0.51 4178 390 2.3 0.15 4062 158 1.4 2.1 17503 391 1.40.90 4046 159 3.4 4.5 455 392 24 13 8839 160 0.56 0.57 1279 393 1.4 0.518732 161 2.4 4.6 293 394 1.6 1.0 13706 162 1.3 1.0 2152 395 44 6.6 17520163 0.39 0.87 1321 396 99 19 >50000 164 6.2 4.6 1800 397 48 30 43179 1650.40 0.62 905 398 7.2 1.9 46809 166 0.41 0.18 3343 399 409 4.1 >50000167 2.6 0.49 4329 400 82 1.6 >50000 168 3.6 4.5 17459 401 27 4.4 6437169 0.36 0.33 1731 402 30 4.4 5969 170 0.42 0.71 2291 403 25 1.7 9265171 0.43 0.12 1964 404 32 4.0 5807 172 4.4 0.75 2652 405 46 15 17055 1731.5 0.54 653 406 8.4 4.8 937 174 0.78 0.67 7716 407 47 828 35363 175 236.4 7938 408 16 61 12421 176 16 18 325 409 2.5 3.4 >50000 177 8.7 4.0549 410 15 1.3 >50000 178 7.0 2.7 321 411 9.6 0.18 11154 179 20 7.0 486412 6.7 0.29 5739 180 1.3 9.6 664 413 29 6.1 >50000 181 1.5 5.0 6552 41441 6.2 >50000 182 3.8 11 18769 415 26 5.2 >50000 183 1.8 3.4 2446 416 101.7 1729 184 1.9 7.9 1871 417 16 13 >50000 185 6.2 7.8 1553 418 19 2.26014 186 12 6.6 26512 419 32 1.4 5905 187 2.1 2.0 1526 421 16 12 >50000188 1.6 0.21 5163 422 3.1 2.0 6817 189 20 16 30736 423 5.4 0.59 42520190 0.77 0.22 874 424 6.3 0.39 17690 191 0.91 1.1 3501 425 13 17 >50000192 5.3 3.9 3143 426 30 0.54 >50000 193 0.84 0.40 1252 427 35 37 >50000194 5.3 2.6 575 428 12 1.1 39542 195 5.2 3.0 577 429 9.3 2.3 >50000 1963.0 1.1 2079 430 5.9 0.27 6111 197 0.30 0.44 1572 431 3.5 0.32 8176 1982.4 2.6 1151 432 102 2.7 >50000 199 0.83 2.0 1211 433 3.0 0.32 6914 2003.0 1.1 8782 434 90 48 >50000 201 0.49 0.52 1788 436 1.8 5.1 10338 2020.35 1.2 2459 437 2.6 6.4 7666 203 27 9.3 513 438 25 13 >50000 204 6.63.1 466 439 7.1 4.3 11236 205 1.2 0.55 600 440 11 62 >50000 206 9.2 13260 441 4.0 11 7321 207 5.3 7.7 437 442 2.5 7.1 7489 208 12 16 276 4434.0 9.3 6551 209 29 97 1078 444 5.0 6.7 19901 210 34 6.6 1080 445 1325 >50000 211 41 44 2253 446 18 21 >50000 212 1.6 3.8 2082 447 1132 >50000 213 1.5 3.0 517 448 28 22 >50000 214 7.5 16 2071 449 37171 >50000 215 4.2 3.7 1996 450 12 39 >50000 216 14 12 4647 451 2.6 5.7792 217 3.4 4.4 7599 452 4.8 11 12564 218 0.82 0.60 4744 453 1634 >50000 219 0.85 0.56 1893 454 0.05 0.05 10860 220 0.74 0.35 4536 4550.59 0.17 14561 221 1.1 0.70 2574 456 5.7 1.6 16284 222 3.2 2.7 5774 4573.2 2.5 21953 223 2.7 2.4 1110 458 2.5 1.2 16792 224 0.40 0.62 679 4591.6 0.54 13834 225 4.0 1.4 4699 460 10 4.4 >50000 226 0.51 0.73 1292 4615.4 1.5 9015 227 1.9 2.6 4322 462 1.1 1.5 1974 228 1.5 2.6 812 463 9.05.2 38772 229 8.7 4.2 1458 464 7.3 2.6 43951 230 0.41 0.77 1703 465 8.53.1 47913 231 5.9 6.6 4167 466 16 2.5 47526 232 11 3.2 4496 467 2.8 1.417054 233 2.7 3.6 1161 468 43 50 >50000 234 13 2.6 733 469 13 3.5 47935235 0.24 1.0 2207 470 4.9 0.49 15491 236 0.66 1.1 939 471 27 2.7 >50000237 1.6 0.95 2072 472 5.3 0.92 46640

What is claimed is:
 1. (canceled)
 2. (canceled)
 3. (canceled) 4.(canceled)
 5. (canceled)
 6. (canceled)
 7. (canceled)
 8. (canceled) 9.(canceled)
 10. (canceled)
 11. A compound of Formula (I)

N-oxide, or a salt thereof, wherein: G is: (i)

or (ii)

A is: (i) —O-L₁-R₆; (ii) —NR₇R₈; (iii) -L₂-C(O)NR₉R₁₀; (iv) —CHR_(x)R₁₁,—CH₂CH₂R₁₁, —CH₂NH₂, —CH₂NHC(O)R₁₁, —CH₂NHC(O)CH₂CH₂(piperidinyl),—CH₂NHC(O)OCH₂(piperidinyl), or —CH₂NHC(O)CH₂CH₂N(CH₃)₂; (v) —CHR₁₂R₁₃,wherein R₁₂ and R₁₃ together with the carbon atom to which they areattached form a cyclic group selected from azabicyclo[4.1.1]octanyl,azepanyl, azetidinyl, C₃₋₆ cycloalkyl, diazaspiro[4.5]decanonyl,morpholinyl, octahydrocyclopenta[c]pyrrolyl, piperidinyl, pyrrolidinyl,and quinuclidinyl, each substituted with zero to 3 R_(12a); (vi)—CH═CH(piperidinyl); or (vii) an aromatic group selected from[1,2,4]triazolo[1,5-a]pyridinyl, imidazo[1,2-a]pyridinyl, imidazolyl,indazolyl, isoquinolinyl, oxadiazolyl, oxazolyl, phenyl, pyrazinyl,pyrazolo[3,4-b]pyridinyl, pyrazolyl, pyridazinyl, pyridinyl,pyrimidinyl, pyrrolyl, quinolinonyl, quinolinyl, quinoxalinyl,tetrahydro-[1,2,4]triazolo[1,5-a]pyrazinyl,tetrahydroimidazo[1,2-a]pyrazinyl, tetrahydroisoquinolinyl,tetrahydrothiazolo[5,4-c]pyridinyl, tetrahydrothieno[2,3-c]pyridinyl,thiadiazolyl, thiazolyl, thiooxadiazolyl, and triazolyl, eachsubstituted with zero to 2 R_(14a) and zero to 3 R_(14b); L₁ is bond,—CH₂—, —CH₂CH₂—, —CH₂C(O)—, —CH₂C(O)NH—, —CH₂C(O)N(CH₃)—,—CH₂C(O)NHCH₂—, or —CH₂C(O)NHCH₂CH₂—; L₂ is a bond, —CH(CH₃)—,—C(CH₃)₂—, or —CH₂CH₂—; R₁ is H, Cl, —CN, C₁₋₄ alkyl, C₁₋₂ fluoroalkyl,C₁₋₂ hydroxyalkyl, or —C(O)O(C₁₋₂ alkyl); each R₂ is independently F,Cl, —CN, —OH, C₁₋₃ alkyl, C₁₋₂ fluoroalkyl, C₁₋₂ cyanoalkyl, C₁₋₃hydroxyalkyl, C₁₋₂ aminoalkyl, —(CH₂)₀₋₂O(C₁₋₃ alkyl), C₃₋₆ cycloalkyl,—NR_(x)R_(x), —(CH₂)₀₋₂C(O)NR_(x)R_(x), —(CH₂)₀₋₂S(O)₂(C₁₋₃ alkyl),—CH₂(C₃₋₆ cycloalkyl), —CH₂(phenyl), or phenyl; each R₅ is independentlyF, Cl, —CN, C₁₋₂ alkyl, or —OCH₃; R₆ is: (i) —CH₂C(O)NHCH₂C(CH₃)₂OH,—CH₂C(O)NHCH₂CH₂C(CH₃)₂OH, —CH₂C(O)NHCH₂CH₂NH₂, or—CH₂C(O)NHCH₂CHFC(CH₃)₂OH; or (ii) azabicyclo[3.2.1]octanyl,azaspiro[5.5]undecanyl, azetidinyl, cyclohexyl,diazabicyclo[2.2.1]heptanyl, diazaspiro[3.5]nonanyl, morpholinyl,octahydrocyclopenta[c]pyrrolyl, piperazinyl, piperidinyl, pyrrolidinyl,or quinuclidinyl, each substituted with zero to 2 R_(6a); each R_(6a) isindependently F, —OH, —CH₃, —CH₂CH₂CH₃, —C(CH₃)₂, —CH₂CH(CH₃)₂,—CH₂CH₂CH₂CF₃, —CH₂CH₂OH, —CH₂CH₂CH₂OH, —CH₂CH(CH₃)OH, —CH₂C(CH₃)₂OH,—CH₂CH₂OCH₃, —NH₂, —N(CH₃)₂, —CH₂NH₂, —CH₂CH₂NH₂, —CH₂CH₂S(O)₂CH₃,—CH₂C(O)N(CH₃)₂, —C(O)CH₂N(CH₃)₂, oxetanyl, tetrahydropyranyl,piperidinyl, isobutylpiperidinyl, or —O(piperidinyl); R₇ is: (i)—CH₂(isopropyl azaspiro[3.5]nonanyl), —CH₂(methylpyrrolidinyl),—C(O)(CH₂)₁₋₃NH₂, —C(O)CH(NH₂)CH₂CH₂CH₃, —C(O)CH(NH₂)CH₂CH(CH₃)₂,—C(O)CH(NH₂)CH(CH₃)CH₂CH₃, —C(O)CH(NH₂)CH₂CH₂C(O)OH,—C(O)CH(NH₂)(CH₂)₃₋₄NH₂, —C(O)CH(NH₂)(CH₂)₁₋₂C(O)NH₂,—C(O)CH(NH₂)(cyclohexyl), —C(O)CH(NH₂)(phenyl), —C(O)(aminocyclohexyl),—C(O)(morpholinyl), —C(O)(pyrrolidinyl), pentamethylpiperidinyl,methylpiperidinyl-piperidinyl, methylpyrrolidinyl-pyrrolidinyl, orphenyl substituted with —OCH₂CH₂(pyrrolidinyl) or —OCH₂CH₂NHCH₂CH₃; or(ii) cyclohexyl substituted with —NR_(x)(CH₂)₂₋₃N(CH₃)₂, —NHCH₂CH₂NHCH₃,—NH(methylpiperidinyl), —NH(CH₂)₂₋₃(morpholinyl), dimethylaminopiperidinyl, or piperazinyl substituted with —CH₃, —CH₂CH₃, —C(CH₃)₃,—CH₂CH(CH₃)₂, —C(O)CH₃, —CH₂CH₂OCH₃, —CH₂(methylphenyl),—(CH₂)₂₋₃(pyrrolidinyl), cyclopentyl, pyridinyl, or methylpiperidinyl;R_(7b) is: (i) C₁₋₄ alkyl, C₁₋₂ fluoroalkyl, C₁₋₂ cyanoalkyl, C₃₋₄hydroxyalkyl, —CH₂CH₂CH₂C≡CH, —CH₂CH₂OCH₃, —CH₂CH₂S(O)₂CH₃,—(CH₂)₁₋₂NR_(x)R_(x), —CH₂C(O)NR_(x)R_(x), —NR_(x)R_(y), —NR_(x)(C₁₋₄hydroxyalkyl), —NR_(x)(CH₂CR_(x)R_(x)OCH₃), —NR_(y)(C₁₋₂ cyanoalkyl),—NR_(x)(C₁₋₂ fluoroalkyl), —NR_(x)(C₂₋₅ hydroxyfluoroalkyl),—NR_(x)(CH₂)₁₋₂C(O)NR_(x)R_(x), —NR_(x)(CH₂)₁₋₃NR_(x)R_(x),—NR_(x)CH₂CH₂N(CH₃)₂, —NR_(x)C(O)(CH₂)₁₋₂NR_(x)R_(x), —OCH₂CH₂N(CH₃)₂,—C(O)(C₁₋₃ alkyl), —C(O)CH₂NR_(x)R_(x), —S(O)₂CH₃, —(CH₂)₁₋₂R_(7d),—CH₂C(O)R_(7d), —C(O)CH₂R_(7d), —NHR_(7d), —NH(CH₂)₁₋₂R_(7d), or—OR_(7d); or (ii) azepanyl, azetidinyl, bicyclo[1.1.1]pentanyl, C₄₋₆cycloalkyl, diazepanyl, dioxothiomorpholinyl, morpholinyl,oxaazaspiro[3.3]heptanyl, oxetanyl, piperazinonyl, piperazinyl,piperidinyl, pyridinyl, pyrrolidinonyl, pyrrolidinyl, tetrahydrofuranyl,tetrahydroisoquinolinyl, or tetrahydropyranyl, each substituted withzero to 1 R_(8a) and zero to 3 R_(8b); each R_(7c) is independently —CH₃or —CH₂CN; R_(7d) is azaspiro[3.5]nonanyl, bicyclo[1.1.1]pentanyl, C₃₋₆cycloalkyl, morpholinyl, oxetanyl, phenyl, piperidinyl, pyrazolyl,pyrrolidinyl, tetrahydrofuranyl, or tetrahydropyranyl, each substitutedwith zero to 1 substituent selected from C₁₋₃ alkyl, —NH₂, —C(O)CH₃,methylpiperidinyl, methylpyrrolidinyl, tetramethylpiperidinyl,—OCH₂CH₂(pyrrolidinyl), and —OCH₂CH₂NHCH₂CH₃; and zero to 4 substituentsselected from —CH₃; R₈ is H, —CH₃, or —CH₂CH₃; or R₇ and R₈ togetherwith the nitrogen atom to which they are attached form a heterocyclicring selected from azetidinyl, diazepanonyl, diazepanyl,diazaspiro[3.3]heptanyl, diazaspiro[3.3]heptanyl,diazaspiro[3.5]nonanyl, diazaspiro[5.5]undecanyl, imidazolidinonyl,octahydro-1H-pyrrolo[3,4-b]pyridinyl, piperazinyl, piperidinyl,pyrrolidinonyl, and pyrrolidinyl, wherein said heterocyclic ring issubstituted with zero to 1 R_(7b) and zero to 2 R_(7c); R_(8a) is —OH,—CH₃, —CH₂CH₃, —CH(CH₃)₂, —C(CH₃)₃, —CH₂CH(CH₃)₂, —CH₂CH₂OCH₃,—CH₂CH₂CF₃, —C(O)CH₃, —CH₂(cyclopropyl), —CH₂(methyl phenyl),—(CH₂)₂₋₃(pyrrolidinyl), —CH₂(methylpyrazolyl), —CH₂(thiophenyl),—NR_(x)R_(x), cyclopentyl, methylpiperidinyl, or pyridinyl; each R_(8b)is —CH₃; R₉ is —CH₃, —CH₂CH₂OH, —CH₂C(CH₃)₂OH, —CH₂C(CH₃)₂CH₂OH,—CH₂CHFC(CH₃)₂OH, —CH₂CH₂C(CH₃)₂OH, —CH(CH₂OH)₂, —CH₂CH₂OCH₃,—CH₂CH₂NH₂, —CH₂CH₂N(CH₃)₂, —CH₂CH₂CH₂N(CH₃)₂, —CH₂CH₂C(O)NH₂,—CH₂S(O)₂OH, —CH₂CH₂C(CH₃)₂NHS(O)₂CH₃, or —(CH₂)₀₋₃R_(9a); R_(9a) iscyclohexyl, cycloheptyl, furanyl, phenyl, piperazinyl, piperidinyl,pyrazolyl, pyridinyl, pyrrolidinyl, quinuclidinyl, thiazolyl, oroctahydrocyclopenta[c]pyrrolyl, each substituted with zero to 2substituents independently selected from —OH, C₁₋₃ alkyl, —NH₂,—N(CH₃)₂, oxetanyl, phenyl, piperazinyl, piperidinyl, and pyrrolidinyl;R₁₀ is H, —CH₃, —CH₂CH₃, —CH₂CH₂OCH₃, or cyclopropyl; or R₉ and R₁₀together with the nitrogen atom to which they are attached form aheterocyclic ring selected from azabicyclo[3.1.1]heptanyl,azaspiro[5.5]undecanyl, diazabicyclo[2.2.1]heptanyl,diazabicyclo[3.1.1]heptanyl, diazabicyclo[3.2.0]heptanyl,diazaspiro[3.5]nonanyl, diazaspiro[4.4]nonanyl, diazaspiro[4.5]decanyl,diazepanyl, indolinyl, morpholinyl, octahydropyrrolo[3,4-c]pyrrolyl,piperazinonyl, piperazinyl, piperidinyl, and pyrrolidinyl, eachsubstituted with zero to 2 R_(10a); each R_(10a) is independently —CH₃,—CH₂CH₃, —CH(CH₃)₂, —CH₂OH, —CH₂CH₂OH, —CH₂OCH₃, —CH₂CH₂OCH₃, —CH₂NH₂,—CH₂CH₂NH₂, —CH₂CH₂NH(CH₃), —CH₂C(O)NH(CH₃), —CH₂C(O)N(CH₃)₂,—CH₂(methyltriazolyl), —CH₂CH₂(phenyl), —CH₂CH₂(morpholinyl), —C(O)CH₃,—C(O)NH₂, —C(O)N(CH₂CH₃)₂, —C(O)CH₂NH(CH₃), —C(O)CH₂N(CH₃)₂, —NH₂,—N(CH₃)₂, —NHC(O)CH₃, —C(O)(furanyl), —O(piperidinyl),—C(O)CH₂(diethylcarbamoylpiperidinyl), methylpiperazinyl, piperidinyl,methylpiperidinyl, diethylcarbamoylpiperidinyl, isopropylpiperidinyl,pyridinyl, trifluoromethylpyridinyl, pyrimidinyl, ordihydrobenzo[d]imidazolonyl; R₁₁ is azetidinyl, azaspiro[3.5]nonanyl,dioxidothiomorpholinyl, hexahydropyrrolo[3,4-c]pyrrolyl, morpholinyl,piperazinyl, piperidinyl, or pyrrolidinyl, each substituted with zero to2 substituents independently selected from F, —CH₃, —CH(CH₃)₂, —CH₂CN,—CH₂(phenyl), —C(O)CH₂N(CH₃)₂, —CH₂C(CH₃)₂OH, —CH₂C(O)N(CH₃)₂,—CH₂CH₂S(O)₂CH₃, —CH₂CH₂S(O)CH₃, oxetanyl, and tetrahydropyranyl; eachR_(12a) is independently —OH, —CH₃, —CH₂CH₂CH₃, —CH(CH₃)₂, —CH₂CH(CH₃)₂,—CF₃, —CH₂CF₃, —CH₂CH₂CH₂CF₃, —CH₂CN, —CH₂C(CH₃)₂OH, —CH₂CH₂OCH₃,—CH₂C(O)NH(CH₃), —CH₂C(O)N(CH₃)₂, —CH₂C(O)NH₂, —CH₂CH₂S(O)₂CH₃,—CH₂CH₂NHS(O)₂CH₃, —CH₂NR_(x)R_(x), —CH₂CH₂NH(CH₃), —OCH₃, —NR_(x)R_(y),—NR_(x)(C₂₋₄ fluoroalkyl), —NR_(x)(CH₂CHFC(CH₃)₂OH),—NR_(x)(CH₂CR_(x)R_(x)OCH₃), —NH(CH₂CN), —N(CH₃)CH₂N(CH₃)₂,—NR_(x)(CH₂CHFC(CH₃)₂OH), —NH(CH₂CH₂OCH₃), —NH(CH₂C(CH₃)₂OH),—NR_(x)(CH₂C(O)NR_(x)R_(x)), —N(CH₃)(OCH₃), —NR_(x)CH₂CH₂S(O)₂CH₃,—NHC(O)CH₃, —NHC(O)CH₂CF₃, —NHC(O)CHR_(x)NH(CH₃), —NR_(x)C(O)CH₂N(CH₃)₂,—NHC(O)CH₂N(CH₃)(CH₂CH₃), —NHC(O)CH₂N(CH₂CH₃)₂,—NHC(O)CH₂NH(CH₂C(CH₃)₂OH), —NHCH₂C(O)NR_(x)(CH₃), —NHS(O)₂CH₃,—C(O)C(CH₃)₃, —C(O)CH(CH₂CH₃)₂, —C(O)CH₂OCH₃, —C(O)CH₂CH₂OCH₃,—C(O)CH₂NH(CH₃), —C(O)CH₂N(CH₃)₂, —C(O)CH(CH₃)NH(CH₃),—C(O)CH₂N(CH₃)(CH₂CH₃), —C(O)CH₂N(CH₂CH₃)₂, R_(12b), —CH₂R_(12b),—C(O)R_(12b), —C(O)CH₂R_(12b), —C(O)CH₂NHR_(12b), —C(O)NR_(x)R_(12b),—NR_(x)C(O)CH₂R_(12b), —NR_(x)R_(12b), —N(CH₂CN)R_(12b),—NR_(x)CH₂R_(12b), —N(CH₂CN)R_(12b), —NHC(O)CH₂NR_(x)R_(12b),—NHC(O)CH₂NR_(x)CH₂R_(12b), —NHCH₂C(O)NHR_(12b), or —OR_(12b); or twoR_(12a) and the carbon atom to which they are attached form C═O; R_(12b)is azetidinyl, bicyclo[1.1.1]pentanyl, cyclopropyl,diazabicyclo[2.2.1]heptanyl, dioxolanyl, dioxidotetrahydrothiopyranyl,dioxidothiomorpholinyl, imidazolyl, morpholinyl,octahydrocyclopenta[c]pyrrolyl, octahydropyrrolo[3,4-c]pyrrolyl,oxaazaspiro[3.3]heptanyl, oxetanyl, phenyl, piperazinyl, piperazinonyl,piperidinyl, pyridinyl, pyrrolidinyl, quinuclidinyl, tetrahydrofuranyl,tetrahydropyranyl, or triazolyl, each substituted with zero to 4substituents independently selected from F, —OH, —CH₃, —CH(CH₃)₂,—CH₂OH, —OCH₃, —CH₂CH₂OCH₃, —NR_(x)R_(x), —C(O)NH₂, and —CH₂S(O)₂CH₃;each R_(14a) is independently: (i) H, F, Cl, —OH, —CH₃, —CH(CH₃)₂,—CH(CH₃)(CH₂CH₃), —CH₂CH₂CH₂C(CH₃)₂, —CF₃, —CH₂CF₃, —CH₂OH, —OCH₃,—CH₂CH₂OCH₃, —CHR_(x)NR_(x)(CH₃), —CH₂N(CH₃)(CH(CH₃)₂),—CH₂NH(CH₂C(CH₃)₃), —CH₂NH(CH₂CN), —CH₂N(CH₃)(CH₂CH₂OCH₃),—CH₂N(CH₂CH₂OCH₃)₂, —CH₂NR_(x)(CH₂C≡CH), —CH₂NHCH₂CH₂N(CH₃)₂,—CH₂CH₂NR_(x)(CH₃), —CH₂CR_(x)(CH₃)NH₂, —CH₂CH₂CH₂N(CH₃)₂,—CH₂CH₂CH₂CH₂NH₂, —CH(NH₂)(CH₂)₃₋₄NH₂, —CH₂NHCH₂CH₂O(C₁₋₃ alkyl),—CH₂NHCH₂CH₂OCH₂CH₂OH, —CH₂NHCH₂CH₂S(O)₂OH, —CH₂C(O)NR_(x)(CH₃),—NR_(x)R_(x), —NH(CH(CH₃)₂), —NHCH₂CH₂NH(CH₃), —NHCH₂CH₂CH₂N(CH₃)₂,—NHC(O)CH₃, —NHC(O)CF₃, —NHC(O)OC(CH₃)₃, —NHC(O)CH₂N(CH₃)₂,—NHC(O)CH₂CH₂N(CH₃)₂, —NHCH₂C(O)CH₂NH(CH₃), —C(O)CH₃, —C(O)CH₂CH(CH₃)OH,—C(O)CH₂NR_(x)(CH₃), —C(O)NR_(x)R_(x), —C(O)NH(CH₂CN),—C(O)NHCH₂CH₂CH₂NR_(x)R_(x), —C(O)NHCH₂CH(CH₃)CH₂NH₂, —C(O)NHCH₂C(O)NH₂,—C(O)N(CH₃)CH₂CH₂CH₂N(CH₃)₂, —C(O)N(CH₂CH₃)CH₂CH₂N(CH₃)₂,—OCH₂CH₂CH₂N(CH₃)₂, —C(O)NHCH₂CH₂NHC(O)CH₃, —S(O)₂NH₂, or—C(O)CH₂S(O)₂CH₃; (ii) 8-azabicyclo[3.2.1]octanyl, azaspiro[3.5]nonanyl,azetidinyl, benzo[c][1,2,5]oxadiazolyl, cyclopentyl, cyclohexyl,diazepanyl, morpholinyl, phenyl, piperazinyl, piperidinyl, pyrazolyl,pyridinyl, pyrrolidinonyl, quinolinyl, quinuclidinyl,tetrahydroisoquinolinyl, tetrahydropyridinyl, or thiazolidinyl, eachsubstituted with zero to 2 substituents independently selected from—CH₃, —CH(CH₃)₂, —CH₂CH(CH₃)₂, —CF₃, —CH₂CH₂CF₃, —CH₂CH₂OH,—CH₂CH₂CH(CH₃)OH, —NH₂, —CH₂N(CH₃)₂, —CH₂CH₂NH(CH₃), —C(O)CH₃,—C(O)CH₂NH(CH₃), —C(O)CH₂N(CH₃)₂, —C(O)O(C(CH₃)₃), —CH₂C(O)NR_(x)(CH₃),cyclobutyl, cyclopentyl, —CH₂(phenyl), —CH₂(pyrrolyl),—CH₂(morpholinyl), —CH₂(methylpiperazinyl), —CH₂(thiophenyl),methylpiperidinyl, isobutylpiperidinyl, and pyridinyl; or (iii)-L₃-R_(14c); each R_(14b) is —CH₃; L₃ is —(CH₂)₁₋₃—, —CH(CH₃)—,—CH(NH₂)—, —CH₂NH—, —C(O)—, —C(O)NH(CH₂)₀₋₄—, —C(O)N(CH₃)CH₂CH₂—, —NH—,—NHC(O)—, —NHCH₂—, —NHCH₂C(O)—, —O—, or —OCH₂CH₂—; R_(14c) isadamantanyl, azetidinyl, cyclopropyl, cyclohexyl, diazepanyl,imidazolyl, indolyl, morpholinyl, octahydropyrrolo[3,4-c]pyrrolyl,phenyl, piperazinonyl, piperazinyl, piperidinyl, pyridinyl,pyrrolidinonyl, pyrrolidinyl, or tetrazolyl, each substituted with zeroto 1 substituent selected from —OH, —CH₃, —CH(CH₃)₂, —CH₂CH(CH₃)₂,—C(CH₃)₂OH, —NH₂, —N(CH₃)₂, —NH(C(CH₃)₂, —NHC(O)CH₃, —C(O)CH₃, —C(O)NH₂,—C(O)N(CH₂CH₃)₂, —C(O)(tetrahydrofuranyl), —C(O)OCH₂CH₃,—CH₂C(O)NH(CH(CH₃)₂, morpholinyl, methylpiperidinyl, pyrazinyl,pyridinyl, and pyrrolidinyl; each R_(x) is independently H or —CH₃; eachR_(y) is independently H or C₁₋₆ alkyl; n is zero or 1; and p is zero,1, 2, or
 3. 12. The compound according to claim 11, N-oxide, or a saltthereof, wherein: A is: (i) —NR₇R₈ wherein R₇ and R₈ together with thenitrogen atom to which they are attached form a heterocyclic ringselected from piperazinyl, piperidinyl, or diazaspiro[3.3]heptanyl,wherein said heterocyclic ring is substituted with zero to 1 R_(7b) andzero to 1 R_(7c); or (ii) —CHR₁₂R₁₃, wherein R₁₂ and R₁₃ together withthe carbon atom to which they are attached form a cyclic group selectedfrom cyclopentyl, cyclohexyl, morpholinyl, or piperidinyl, eachsubstituted with zero to 1 R_(12a); R₁ is —CH₃ or —CH(CH₃)₂; each R₂ isindependently —CH₃ or —OCH₃; R₅ is F, Cl, or —CH₃; R_(7b) is: (i) —CH₃,—CH₂CH₃, —CH₂CH₂CH₃, —CH(CH₃)₂, —CH₂CH(CH₃)₂, —CH₂CF₃, —CH₂CN,—CH₂C(CH₃)₂OH, —CH₂CH₂OCH₃, —CH₂CH₂S(O)₂CH₃, —(CH₂)₁₋₂NR_(x)R_(x),—CH₂C(O)NR_(x)R_(x), —NR_(x)R_(y), —NR_(x)(C₁₋₄ hydroxyalkyl),—NH(CH₂CR_(x)R_(x)OCH₃), —NR_(y)(C₁₋₂ cyanoalkyl), —NR_(x)(C₁₋₂fluoroalkyl), —NR_(x)(C₂₋₅ hydroxyfluoroalkyl),—NR_(x)(CH₂)₁₋₂C(O)NR_(x)R_(x), —NR_(x)(CH₂)₁₋₃NR_(x)R_(x),—NR_(x)CH₂CH₂N(CH₃)₂, —NR_(x)C(O)(CH₂)₁₋₂NR_(x)R_(x), —C(O)CH₃,—C(O)CH₂NR_(x)R_(x), —S(O)₂CH₃, —(CH₂)₁₋₂R_(7d), —CH₂C(O)R_(7d),—C(O)CH₂R_(7d), —NHR_(7d), —NH(CH₂)₁₋₂R_(7d), or —OR_(7d); or (ii)azetidinyl, cyclobutyl, dioxothiomorpholinyl, morpholinyl,oxaazaspiro[3.3]heptanyl, oxetanyl, piperazinonyl, piperazinyl,piperidinyl, tetrahydrofuranyl, or tetrahydropyranyl, each substitutedwith zero to 1 R_(8a); R_(7c) is —CH₃; R_(8a) is —CH₃, —CH(CH₃)₂, or—S(O)₂CH₃; R_(12a) is —CH(CH₃)₂, —CH₂CF₃, —CH₂C(CH₃)₂OH, —CH₂CH₂OCH₃,—CH₂C(O)NH(CH₃), —CH₂C(O)N(CH₃)₂, —CH₂C(O)NH₂, —CH₂CH₂S(O)₂CH₃,—CH₂CH₂NH(CH₃), —NR_(x)R_(y), —NR_(x)(C₂₋₄ fluoroalkyl),—NH(CH₂C(CH₃)₂OH), —NH(CH₂CHFC(CH₃)₂OH), —NH(CH₂CH₂OCH₃),—NH(CH₂C(CH₃)₂₀CH₃), —NR_(x)(CH₂C(O)NR_(x)R_(x)), —C(O)CH₂NH(CH₃),—C(O)CH₂N(CH₃)₂, R_(12b), —CH₂R_(12b), —NR_(x)R_(12b), —N(CH₂CN)R_(12b),or —NR_(x)CH₂R_(12b); R_(12b) is azetidinyl, bicyclo[1.1.1]pentanyl,oxaazaspiro[3.3]heptanyl, oxetanyl, piperidinyl, tetrahydrofuranyl, ortetrahydropyranyl, each substituted with zero to 4 substituentsindependently selected from —CH₃, —CH(CH₃)₂, —CH₂OH, or —OCH₃; and n iszero or
 1. 13. The compound according to claim 11, N-oxide, or a saltthereof, wherein: A is: —NR₇R₈ wherein R₇ and R₈ together with thenitrogen atom to which they are attached form a heterocyclic ringselected from piperazinyl, piperidinyl, or diazaspiro[3.3]heptanyl,wherein said heterocyclic ring is substituted with zero to 1 R_(7b) andzero to 1 R_(7c); or R₁ is —CH₃ or —CH(CH₃)₂; each R₂ is independently—CH₃ or —OCH₃; R₅ is F, Cl, or —CH₃; R_(7b) is: (i) —CH₃, —CH₂CH₃,—CH₂CH₂CH₃, —CH(CH₃)₂, —CH₂CH(CH₃)₂, —CH₂CF₃, —CH₂CN, —CH₂C(CH₃)₂OH,—CH₂CH₂OCH₃, —CH₂CH₂S(O)₂CH₃, —(CH₂)₁₋₂NR_(x)R_(x), —CH₂C(O)NR_(x)R_(x),—NR_(x)R_(y), —NR_(x)(C₁₋₄ hydroxyalkyl), —NH(CH₂CR_(x)R_(x)OCH₃),—NR_(y)(C₁₋₂ cyanoalkyl), —NR_(x)(C₁₋₂ fluoroalkyl), —NR_(x)(C₂₋₅hydroxyfluoroalkyl), —NR_(x)(CH₂)₁₋₂C(O)NR_(x)R_(x),—NR_(x)(CH₂)₁₋₃NR_(x)R_(x), —NR_(x)CH₂CH₂N(CH₃)₂,—NR_(x)C(O)(CH₂)₁₋₂NR_(x)R_(x), —C(O)CH₃, —C(O)CH₂NR_(x)R_(x),—S(O)₂CH₃, —(CH₂)₁₋₂R_(7d), —CH₂C(O)R_(7d), —C(O)CH₂R_(7d), —NHR_(7d),—NH(CH₂)₁₋₂R_(7d), or —OR_(7d); or (ii) azetidinyl,bicyclo[1.1.1]pentanyl, cyclobutyl, dioxothiomorpholinyl, morpholinyl,oxaazaspiro[3.3]heptanyl, oxetanyl, piperazinonyl, piperazinyl,piperidinyl, tetrahydrofuranyl, or tetrahydropyranyl, each substitutedwith zero to 1 R_(8a); R_(7c) is —CH₃; R_(8a) is —CH₃, —CH(CH₃)₂, or—S(O)₂CH₃; and n is zero or
 1. 14. The compound according to claim 11,N-oxide, or a salt thereof, wherein: A is: —CHR₁₂R₁₃, wherein R₁₂ andR₁₃ together with the carbon atom to which they are attached form acyclic group selected from cyclopentyl, cyclohexyl, morpholinyl, orpiperidinyl, each substituted with zero to 1 R_(12a); R₁ is —CH₃ or—CH(CH₃)₂; each R₂ is independently —CH₃ or —OCH₃; R₅ is F, Cl, or —CH₃;R_(12a) is —CH(CH₃)₂, —CH₂CF₃, —CH₂C(CH₃)₂OH, —CH₂CH₂OCH₃,—CH₂C(O)NH(CH₃), —CH₂C(O)N(CH₃)₂, —CH₂C(O)NH₂, —CH₂CH₂S(O)₂CH₃,—CH₂CH₂NH(CH₃), —NR_(x)R_(y), —NR_(x)(C₂₋₄ fluoroalkyl),—NH(CH₂C(CH₃)₂OH), —NH(CH₂CHFC(CH₃)₂OH), —NH(CH₂CH₂OCH₃),—NH(CH₂C(CH₃)₂₀CH₃), —NR_(x)(CH₂C(O)NR_(x)R_(x)), —C(O)CH₂NH(CH₃),—C(O)CH₂N(CH₃)₂, R_(12b), —CH₂R_(12b), —NR_(x)R_(12b), —N(CH₂CN)R_(12b),or —NR_(x)CH₂R_(12b); R_(12b) is azetidinyl, bicyclo[1.1.1]pentanyl,oxaazaspiro[3.3]heptanyl, oxetanyl, piperidinyl, tetrahydrofuranyl, ortetrahydropyranyl, each substituted with zero to 4 substituentsindependently selected from —CH₃, —CH(CH₃)₂, —CH₂OH, or —OCH₃; and n iszero or
 1. 15. The compound according to claim 11, N-oxide, or a saltthereof, wherein: G is: (i)

or (ii)

A is: —NR₇R₈ wherein R₇ and R₈ together with the nitrogen atom to whichthey are attached form a heterocyclic ring selected from piperidinyl,wherein said heterocyclic ring is substituted with zero to 1 R_(7b) andzero to 1 R_(7c); or R₁ is —CH₃ or —CH(CH₃)₂; each R₂ is independently—CH₃; R₅ is F; R_(7b) is: (i) —CH(CH₃)₂, —CH₂CH₂OCH₃,—(CH₂)₁₋₂NR_(x)R_(x), —CH₂C(O)NR_(x)R_(x), —C(O)CH₂NR_(x)R_(x), or—(CH₂)₁₋₂R_(7d); or (ii) oxetanyl or piperidinyl, each substituted withzero to 1 R_(8a); R_(7c) is —CH₃; R_(8a) is —CH₂CH(CH₃)₂; and n is zeroor
 1. 16. The compound according to claim 11, N-oxide, or a saltthereof, wherein said compound is:2-(4-(2-(3,4-dimethoxyphenyl)-3-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)piperidin-1-yl)-N-methylethan-1-amine(8);2-(3,4-dimethoxyphenyl)-5-(1′-isobutyl-[1,4′-bipiperidin]-4-yl)-3-methyl-1H-pyrrolo[2,3-c]pyridine(9);2-(2,6-dimethylpyridin-4-yl)-4-fluoro-3-isopropyl-5-(1-isopropylpiperidin-4-yl)-1H-pyrrolo[2,3-c]pyridine(97);2-(4-(2-(2,6-dimethylpyridin-4-yl)-4-fluoro-3-isopropyl-1H-pyrrolo[2,3-c]pyridin-5-yl)piperidin-1-yl)-N-methylacetamide(150);2-(2,6-dimethylpyridin-4-yl)-4-fluoro-3-isopropyl-5-(piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridine(151);2-(4-(2-(2,6-dimethylpyridin-4-yl)-4-fluoro-3-isopropyl-1H-pyrrolo[2,3-c]pyridin-5-yl)piperidin-1-yl)acetamide(152);2-(4-(2-(2,6-dimethylpyridin-4-yl)-4-fluoro-3-isopropyl-1H-pyrrolo[2,3-c]pyridin-5-yl)piperidin-1-yl)-N,N-dimethylacetamide(153);2-(dimethylamino)-1-(4-(2-(2,6-dimethylpyridin-4-yl)-4-fluoro-3-isopropyl-1H-pyrrolo[2,3-c]pyridin-5-yl)piperidin-1-yl)ethan-1-one(185);1-(4-(2-(2,6-dimethylpyridin-4-yl)-4-fluoro-3-isopropyl-1H-pyrrolo[2,3-c]pyridin-5-yl)piperidin-1-yl)-2-(methylamino)ethan-1-one(214);2-(2,6-dimethylpyridin-4-yl)-4-fluoro-3-isopropyl-5-(1-((3-methyloxetan-3-yl)methyl)piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridine (215);2-(2,6-dimethylpyridin-4-yl)-4-fluoro-3-isopropyl-5-(1-(2-methoxyethyl)piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridine(216); or2-(2,6-dimethylpyridin-4-yl)-4-fluoro-3-isopropyl-5-(1-(oxetan-3-yl)piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridine (251).
 17. A pharmaceuticalcomposition comprising a compound according to claim 11 or apharmaceutically-acceptable salt thereof; and a pharmaceuticallyacceptable carrier.
 18. A method of treating an autoimmune disease or achronic inflammatory disease, comprising administering to a mammalianpatent a compound according to claim 11 or a pharmaceutically acceptablesalt thereof, wherein said autoimmune disease or chronic inflammatorydisease is selected from systemic lupus erythematosus (SLE), rheumatoidarthritis, multiple sclerosis (MS), and Sjögren's syndrome.